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HX641476 
RC660  .F81  1 91 5      Diabetes  mellitus : 


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Columbia  maOmgitf^h 
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Department  nf  Pjgatolojuj 
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DIABETES  MELLITUS 

DESIGNED  FOR  THE  USE  OF 
PRACTITIONERS  OF  MEDICINE 


BY 

NELLIS  B.  FOSTER,  M.D. 

ASSISTANT    PROFESSOR    OF    MEDICINE,    CORNELL    UNIVERSITY 
ASSOCIATE   PHYSICIAN  TO  THE  NEW   YORK  HOSPITAL 


PHILADELPHIA  AND  LONDON 
J.  B.  LIPPINCOTT  COMPANY 


V  ~.*~* 


COPYRIGHT   1915,   BY  J.  B.   LIPPINCOTT   COMPANY 


-   S2>6*\ 


PRINTED  BY  J.   B.  LIPPINCOTT  COMPANY 

AT  THE  WASHINGTON  SQUARE  PRESS 

PHILADELPHIA,    TT.  S.  A. 


Dedicated 
with  affection  and  respect 

TO 

SAMUEL  WALDRON  LAMBERT 


PREFACE 

The  investigations  in  the  pathogenesis  of  diabetes 
that  have  broadened  our  knowledge  in  the  last  decade 
have  given  rise  to  an  enormous  literature.  For  the 
most  part  important  contributions  have  been  printed 
in  those  journals  devoted  to  physiology,  chemistry, 
etc.,  which  are  not  so  commonly  read  by  clinicians.  On 
the  other  hand,  many  of  the  clinical  papers  and  even 
monographs,  too,  are  frankly  partisan  to  some  doc- 
trine that  has  vogue  for  the  moment.  Because  of  this 
it  has  been  impressed  upon  me  that  a  critical  presenta- 
tion of  the  evidence  as  its  exists  at  present  would  be 
of  value  to  my  fellow  clinicians.  The  disparity  in  the 
point  of  view  of  the  pathologist  and  biological  chemist 
from  that  of  the  clinician  seems  to  me  explicable  only 
in  the  lack  of  a  critical  background  for  the  latter. 

With  the  extensive  literature  dealing  with  diabetes 
it  is  of  little  use  to  attempt  a  complete  bibliography. 
It  seemed  better  to  cite  under  each  chapter  those 
papers  which  dealt  exhaustively  with  a  given  subject, 
and  as  these  papers  themselves  contain  many  refer- 
ences the  reader  is  given  access  at  once  to  whatever 
realms  he  may  care  to  explore. 

N.  B.  Foster. 

515  Park  Avenue,  New  York. 

January,  1915.  , 


CONTENTS 


CHAPTER  PAQB 

I.    Normal  Metabolism 1 

II.  Sources  of  Glucose  in  the  Animal  Body  ....       9 

III.  Experimental  Glycosuria 36 

IV.  Acidosis 59 

V.    Pathogenesis 82 

VI.    History 89 

VII.    Etiology 92 

VIII.    Pathology 101 

IX.    Symptomatology 124 

X.    Renal  Diabetes 156 

XI.    Diagnosis  and  Course  of  the  Disease 159 

XII.    Total  Metabolism  in  Diabetes 170 

XIII.  Treatment 181 

XIV.  Identification  of  Sugars  in  Urine 226 


Vll 


DIABETES  MELLITUS 

I 
NORMAL  METABOLISM 

The  functions  of  the  living  cells  represent  chemical 
changes  within  them  are  dependent  upon  an  inter- 
change of  nutrient  and  refuse  material  with  the  sur- 
rounding fluids.  The  sum  of  these  various  complex 
processes  involved  is  termed  metabolism.  The  cellu- 
lar functions  entail  the  expenditure  of  energy  and  also 
the  wearing  out  of  cellular  substances,  and  the  ma- 
terials for  the  replacement  of  these  substances  and  for 
the  total  energy  needs  must  be  furnished  by  food. 
The  food  requirements  of  the  body,  then,  must  cover 
the  demands  for  energy  expended  as  mechanical  work, 
chemical  work  and  heat,  and  also  for  the  replacement 
of  worn-out  tissues. 

Since  the  tissues  are  primarily  composed  of  pro- 
tein, it  is  evident  that  for  their  repair  protein  food  be- 
comes the  chief  essential;  while  either  fats,  carbohy- 
drates, or  protein  can  be  utilized  to  furnish  energy, 
only  the  protein  can  replace  body  tissue.  Fat  and 
carbohydrate  contain  the  elements  carbon,  hydrogen, 

and  oxygen ;  protein  has  these  elements  and  also  nitro- 

1 


2  DIABETES  MELLITUS 

gen,  consequently  nitrogen  is  commonly  employed  as 
the  measure  of  the  protein  economy  of  the  body,  and 
the  sum  of  the  total  metabolism  can  be  estimated  in 
terms  of  carbon  and  nitrogen.  Because  of  the  essen- 
tial nature  of  the  protein  economy  to  the  body  it 
deserves  more  than  passing  notice.  When  protein 
undergoes  digestion  in  the  alimentary  canal  the  resul- 
tant cleavage  products  are  amino-acids,  of  which  leu- 
cine and  tyrosine  are  examples.  The  amino-acids  are 
absorbed  by  the  blood  and  conveyed  to  the  various 
cells,  where  a  resynthesis  into  protein  takes  place. 
This  explains  how  the  body  is  enabled  to  build  up  a 
number  of  different  cellular  proteins,  each  peculiar  to 
some  organ,  out  of  the  aggregate  of  amino-acids  from 
protein  food.  The  process  is  comparable  to  the  vari- 
ous architectural  designs  that  might  be  constructed 
from  a  set  of  toy  blocks,  hence  the  German  term 
Bausteine  (building  stones)  to  designate  these  prod- 
ucts of  protein  hydrolysis.  The  chemical  differences 
between  the  proteins  of  various  organs  rest  in  the 
amino-acids  that  constitute  them.  Having  this  con- 
ception of  protein  anabolism  in  mind,  it  becomes  at 
once  evident  that  the  food  must  contain  the  basis  for  a 
considerable  variety  of  these  acids,  since  the  various 
tissues  have  different  requirements.  When  the  need 
of  a  vital  organ  is  not  met  in  the  food  supply,  some 
less  important  tissue  is  sacrificed  by  nature  to  furnish 


NORMAL  METABOLISM  3 

the  material  demanded;  for  example,  during  starva- 
tion the  heart  protein  is  preserved  at  the  expense  of 
the  skeletal  muscles.  Nitrogenous  food  not  only  re- 
places body  tissue  but  it  may  also  serve  as  a  source  for 
a  large  part  of  the  energy  requirements.  Carnivorous 
animals  are  able  to  do  work  and  maintain  nutrition 
on  a  diet  composed  essentially  of  protein.  That  man 
is  unable  to  do  so  appears  primarily  due  to  his  in- 
ability to  masticate  and  digest  the  amounts  necessary. 
When  protein  food  is  ingested  in  large  amounts  be- 
yond immediate  needs  there  is  no  general  tendency  on 
the  part  of  the  body  to  store  protein  as  is  the  case  with 
fat.  Only  the  carbon  is  stored,  as  the  nitrogen  is  re- 
coverable in  the  urine.  Experiments  which  will  be 
detailed  subsequently  indicate  that  the  carbon  is  saved 
to  the  body  as  glycogen.  This  failure  of  the  tissues  to 
store  protein,  except  during  definite  periods  of  growth 
or  convalescence,  marks  the  chief  peculiarity  of  nitro- 
gen metabolism  in  the  animal  body.  There  is  here  a 
marked  tendency  to  maintain  an  equilibrium  between 
ingest  and  egest  unless  the  amount  of  nitrogenous 
food  is  actually  below  the  needs  for  tissue  repair. 
On  the  other  hand,  when  the  intake  is  excessive  the 
urinary  nitrogen  rises  to  a  higher  level  until  a  balance 
is  struck.  Now  the  explanation  for  this  is  evident  in 
the  chemical  structure  of  protein,  which  may  be  ex- 
pressed as  a  chain  of  amino-acids  the  links  of  which 


4  DIABETES  MELLITUS 

are  broken  in  digestion.  Amino-acids  that  are  not  uti- 
lized for  the  synthesis  of  new  proteins  are  deamidized, 
that  is,  lose  the  NH2  radicle  and  are  thus  transformed 
into  fatty  acids.  The  resultant  ammonia  from  the 
amino-radicle  becomes  united  with  carbon  dioxide  and 
goes  over  into  urea.  Some  of  the  fatty  acids  are 
transformed  into  sugar  and  stored  as  glycogen  or  fat 
if  not  required  as  fuel,  while  others  are  probably  built 
up  into  fatty  compounds  without  the  intervening 
sugar  transformation.  In  this  manner  the  carbon  of 
the  surplus  protein  is  reserved  to  the  body. 

There  are  many  experiments  recorded,  both  on 
man  and  on  animals,  which  illustrate  this  tendency  of 
nitrogen  metabolism  to  establish  an  equilibrium  be- 
tween ingest  and  egest.  When  the  caloric  need  of  the 
body  is  made  good  by  the  use  of  carbohydrates  and 
fat,  the  intake  of  protein  food  may  be  very  small  in- 
deed (6  to  7  grammes  N,  equivalent  to  37  to  44 
grammes  protein),  and  there  then  occurs  a  gradual 
fall  in  the  body's  nitrogen  output  until  a  balance  is 
struck.  Just  how  low  the  protein  metabolism  can  be 
maintained  over  long  periods  without  prejudice  to 
health  is  not  clear.  Some  believe  as  little  as  0.1 
gramme  of  nitrogen  per  kilo  of  body  weight  (50 
grammes  protein  per  day)  is  adequate  for  adults,  but 
this  standard  is  not  generally  accepted  since  it  is  less 
than  half  the  amount  computed  to  be  necessary  by 


NORMAL  METABOLISM  5 

Voit.  Studies  of  the  nitrogen  metabolism  made  upon 
man  and  animals  during  fasting  have  been  very  in- 
structive in  giving  insight  into  the  protein  chemistry 
of  the  body.  During  the  first  few  days  of  the  fasting 
period  there  is  a  slow  fall  in  the  daily  nitrogen  excre- 
tion below  the  amounts  excreted  prior  to  fasting. 
During  this  period  the  body  is  burning  its  glycogen 
stores,  and  when  these  are  consumed  there  is  a  tempo- 
rary rise  in  the  nitrogen  output  which  indicates  that 
body  tissue  is  being  expended.  There  is  then  a 
gradual  fall  to  a  low  level  which  persists  until  death 
approaches.  Between  the  twentieth  and  thirtieth 
days  of  his  fast  Succi  excreted  from  6  to  3.0  grammes 
of  nitrogen  per  day,  a  loss  to  the  body  of  37  to  19 
grammes  of  protein.  As  there  was  at  this  time  no 
glycogen  the  necessary  energy  must  have  been  made 
good  by  body  fat.  When  there  is  a  scant  reserve  of 
fat  in  the  body  the  protein  catabolism  is  higher — 
that  is  to  say,  more  energy  must  be  furnished  by  pro- 
tein, and  in  this  sense  fat  is  a  protein  sparer.  But 
fat  will  not  be  consumed  in  large  amounts  except 
under  those  forced  conditions  of  metabolism  exempli- 
fied in  the  fasting  state.  Carbohydrate  is  much  more 
effective  in  saving  body  protein  from  consumption 
than  is  fat.  Voit  was  able  to  demonstrate  that  while 
ingested  starch  lowered  the  nitrogen  excretion  con- 
siderably, fat  did  so  only  to  a  limited  extent  even 


6  DIABETES  MELLITUS 

when  the  caloric  value  of  the  fat  was  greater  than  that 
of  the  starch.  It  appears,  then,  that  there  is  a  selective 
action  on  the  part  of  the  cells,  and  carbohydrate  is 
burned  by  preference  so  long  as  available  for  the 
necessary  heat  production ;  in  the  absence  of  available 
carbohydrate  fat  will  be  utilized  in  order  to  conserve 
the  more  essential  protein. 

From  this  discussion  it  is  apparent,  first,  that  pro- 
tein is  qualitatively  the  indispensable  food  material 
of  the  body,  and  in  its  absence  actual  tissue  destruc- 
tion occurs  even  though  the  energy  needs  are  met  in 
other  foods ;  second,  that  beyond  the  minimal  require- 
ment of  protein  the  organism  is  able  to  utilize  either 
fat  or  carbohydrate,  and  at  least  qualitatively  it  is 
indifferent  which  of  these  is  available;  and,  finally, 
these  foods  are  capable  of  acting  as  protectors  to  body 
tissue,  saving  it  from  destruction  for  heat  demands. 

The  chief  energy  requirement  of  the  body  is  for 
the  maintenance  of  body  heat.  Rubner  has  shown 
that  almost  the  entire  potential  energy  of  food  leaves 
the  resting  body  as  heat.  Kinetic  energy  and  heat 
are  developed  through  the  oxidation  of  the  various 
nutriment  materials  ingested,  and  this  oxidation  proc- 
ess in  the  animal  body  appears  to  be  very  definite 
and  orderly  and  is  probably  specific  for  each  of  the 
three  food  materials.  Tissue  oxidations  are  seldom  if 
ever  direct  in  the  sense  conceived  by  Lavoisier,  but 


NORMAL  METABOLISM  7 

are  effected  through  the  agency  of  enzymes.  In  the 
case  of  carbohydrate  and  fat  the  end  products  of 
combustion  are  carbon  dioxide  and  water,  while  with 
protein  the  urinary  ingredients  such  as  urea  are  still 
capable  of  yielding  heat  if  oxidized ; 1  that  is  to  say, 
protein  is  not  completely  oxidized,  its  potential  energy 
never  completely  developed,  in  contrast  to  fat  which  is 
burned  to  its  ultimate  end  products. 

As  the  total  energy  of  the  body  is  effected  through 
the  absorption  of  oxygen  and  the  production  of  car- 
bon dioxide  it  is  possible,  by  measuring  the  oxygen 
used  or  the  carbon  dioxide  produced,  to  compute  the 
amount  of  heat  developed  during  a  given  period. 
Commonly  this  energy  is  measured  in  large  calories — 
the  heat  required  to  raise  one  kilogramme  of  water 
1°C.  The  amount  of  heat  produced  by  the  healthy 
resting  body  varies  with  a  number  of  considerations, 
chief  among  which  is  the  size  (surface  area),  radia- 
tion being  relatively  greater  from  small  bodies.  At 
rest  this  amount  is  about  32  calories  per  kilogramme 
body  weight  per  day ;  under  various  degrees  of  activ- 
ity of  course  it  is  proportionately  greater.  There  is 
also  a  wide  variation  in  diseased  states;  with  fever 
metabolism  is  much  increased  and  roughly  propor- 
tionate to  the  rise  in  temperature,  while,  on  the  other 

1  According  to  Rubner  22  to  28  per  cent,  of  the  potential  energy  of 
protein  is  lost  to  the  body  through  this  incomplete  combustion. 


8  DIABETES  MELLITUS 

hand,  in  some  disorders  such  as  myxoedema  the  en- 
ergy requirement  is  below  the  normal. 

With  respect  to  any  morbid  condition,  then,  we 
are  concerned  with  metabolism  from  two  points  of 
view:  first,  quantitatively,  since  only  by  recognizing 
differences  in  the  sum  of  energy  demands  can  we 
arrange  suitable  dietaries  to  furnish  the  energy;  and 
second,  qualitatively.  When  through  the  failure  of 
the  organism  to  utilize  some  nutrient  material  in  the 
normal  way  there  arises  increased  demands  for  other 
forms  of  nourishment,  or  the  by-products  of  the  per- 
verted metabolism  are  in  themselves  injurious;  then 
we  have  conditions  which  not  only  influence  the 
sum  of  the  total  energy  demands  but  also  induce 
many  remote  effects  that  become  manifested  in  a 
clinical  picture.  In  diabetes  mellitus  we  find  both 
qualitative  and  quantitative  changes  in  metabolism, 
and  an  understanding  of  these  is  requisite  to  a  com- 
prehension of  the  disease  and  its  treatment. 


II 

SOURCES  OF  GLUCOSE  IN  THE 
ANIMAL  BODY 

The  fuel  of  the  animal  body  is  chiefly  carbo- 
hydrate. Under  normal  conditions  demand  is  made 
first  upon  the  carbohydrate  stores  to  supply  heat 
and  energy  for  work,  and  so  long  as  these  stores  are 
adequate  there  is  slight  call  upon  protein  or  fat.  The 
latter  may  be  regarded,  so  far  as  metabolism  is  con- 
cerned, as  an  emergency  reserve.  It  is  perfectly 
possible  to  maintain  life  at  least  on  an  adequate  food 
supply  of  starches,  with  just  sufficient  nitrogenous 
food  to  replace  the  wear  and  tear  of  tissue  break- 
down— a  little  over  0.1  gramme  of  nitrogen  per  kilo 
body  weight  per  day.  It  concerns  us  at  present  to  ask 
whence  this  supply  of  carbohydrate  is  derived  under 
various  conditions  of  nutrition. 

The  carbohydrates  in  foods  consist  of  starches 

(and  the  products  of  starch  cleavage,  i.e.,  dextrins) 

and  the  simpler  sugars  such  as  saccharose,  fructose, 

and  glucose.    In  the  course  of  their  transit  through 

the  intestinal  canal  the  more  complex  carbohydrates 

are  broken  down  through  the  agency  of  the  several 

amylolytic  enzymes  into  simple  hexoses   (six  carbon 
2  9 


10  DIABETES  MELLITUS 

sugars).  The  greater  part  of  the  sugars  enter  the 
blood  stream  as  dextrose  and  levulose.  It  remains  de- 
batable whether  any  carbohydrate  is  absorbed  in  a 
more  complex  form  than  glucose ;  if  any,  it  must  be  but 
in  traces  since  the  introduction  into  the  blood  stream  of 
saccharose  is  followed  by  its  excretion  in  the  urine.1 

During  the  period  of  digestion  following  a  meal 
rich  in  carbohydrate  the  portal  blood  leaving  the  in- 
testine contains  much  more  glucose  than  the  blood  as 
it  leaves  the  liver  in  the  hepatic  vein.  The  liver  acts 
as  a  screen,  removing  the  excess  of  glucose  and  storing 
it  as  glycogen,  thereby  protecting  the  general  circula- 
tion and  preventing  loss  through  the  kidneys.  Other 
tissues,  notably  the  muscles,  are  also  capable  of  trans- 
forming glucose  into  glycogen  and  conserving  it  for 
future  needs.  When  the  supply  of  food  is  in  excess 
of  the  immediate  requirements  of  the  organism  the 
glycogen  content  of  the  tissues  may  become  very 
large,  but,  as  will  be  seen,  glycogen  is  not  the  sole 
means  of  disposal  of  superfluous  glucose  since  the 
transformation  of  carbohydrate  into  fat  is  one  of  the 
best  demonstrated  facts  in  physiology.  That  glyco- 
gen may  be  formed  in  the  body  from  ingested  carbo- 
hydrate was  shown  by  the  following  experiment. 
Rabbits  were  kept  without  food  for  such  a  period  as 
experience  had  shown  to  deplete  the  liver  glycogen  to 

1Voit:  Deutsch.  Arch.  f.  klin.  Med.,  1897,  58,  p.  523. 


GLUCOSE  IN  THE  ANIMAL  BODY  11 

an  insignificant  amount;  then  after  feeding  sub- 
stances rich  in  carbohydrate  the  animals  were  killed 
and  the  organs  examined  for  glycogen.  It  was  found 
that  in  rabbits  so  fed  the  livers  contained  much  more 
glycogen  than  the  livers  in  control  animals.2  It  was 
also  shown  that  the  subcutaneous  administration  of 
glucose  caused  an  increase  in  liver-glycogen,3  and 
finally  Grlibe  4  noted  that  the  perfusion  of  the  liver 
with  blood  rich  in  glucose  caused  an  augmentation  of 
glycogen  in  the  liver.  We  know  too,  that  the  muscles 
are  capable  of  forming  glycogen  from  glucose  5  and 
that  the  total  muscle  tissues  can  contain  about  the 
same  amount  as  the  liver. 

At  the  present  time  no  one  questions  the  validity 
of  the  idea  that  glycogen  can  be  formed  from  carbo- 
hydrates. The  biological  principle  in  this  process  is 
worthy  of  note  since  it  is  typical  of  many  transfor- 
mations in  the  animal  body.  Glycogen  is  a  substance 
much  resembling  starch.  It  has  the  elemental  com- 
position and  the  same  formula  (C6Hi0O5)x  and  is 
often  called  animal  starch;  it  differs  from  starch, 
however,  in  many  reactions.  For  the  manufacture 
of  this  substance  from  starch  the  animal  organism 

2Pavy:  Philosophical  Transact,  1860,  p.  579.  Pfliiger:  Das  Glya> 
gen.     Cremer:  Ergeb.  Physiol.,  1902,  p.  803. 

3Voit:  Zeit.  Biol.,  1891,  28,  pp.  245  and  288. 
4  Pfliiger's  Arch.,  1905,  107,  p.  490. 
5Kiilz;  Pfliig.  Arch.,  1881,  24,  p.  64. 


12  DIABETES  MELLITUS 

proceeds  to  break  down  the  latter  polysaccharide  into 
its  simplest  units,  the  hexoses,  and  from  these  by  a 
form  of  synthesis  glycogen  is  built  up.  Disregarding 
the  intermediary  steps  the  reactions  are  these: 

Starch  Glucose 

(C6H10OB)x+H2O  =  x(C6H1206) 
x(C6H1206)  -H20=  (C6H10OB)x 

Glycogen 

This  is  an  example  of  one  of  the  most  characteristic 
biological  reactions,  hydration  and  dehydration,  and 
it  will  often  be  met  with  in  other  relations. 

The  question  arises  at  this  point:  Is  the  glycogen 
derived  from  glucose  the  same  as  that  from  levulose, 
or  are  they  different?  It  is  difficult  to  understand, 
from  a  chemical  point  of  view,  how  dextrose  and 
fructose  can  produce  an  identical  glycogen,  since  the 
former  hexose  is  an  aldose  containing  the  CHO  group 
while  the  latter  is  a  ketose  marked  by  the  CO  group. 
Further,  the  transformation  of  one  sugar  into  the 
other  is  a  difficult  procedure  in  the  laboratory.  Of 
course  it  is  possible  that  these  sugars  may  be  trans- 
formed by  quite  different  processes  and  no  common 
compound  be  formed  until  glycogen  is  produced.  It 
is  often  cited  that  in  pancreatic  diabetes  levulose 
given  in  the  food  can  form  glycogen  in  the  liver, 
while  dextrose  cannot,  but  more  trustworthy  experi- 
ments indicate  that  this  is  incorrect.6 

8  Barrenschecn:  Biochem.  Zeitschr.,  1913,  58,  277. 


GLUCOSE  IN  THE  ANIMAL  BODY  13 

Inasmuch  as  glycogen  is  not  peculiar  to  the  tissues 
$  /of  the  herbivera  it  follows  that  there  must  be  other 
sources  for  it  than  carbohydrate.  At  one  time  this 
subject  was  a  matter  for  no  little  discussion  among 
physiologists,  and  though  it  cannot  be  claimed  at 
present  that  every  step  is  demonstrated,  still  the 
principles  involved  are  generally  accepted.  The  fact 
is  beyond  dispute  that  animals  fed  exclusively  on  pro- 
tein and  fat  store  up  large  amounts  of  glycogen.  At 
one  time  this  glycogen  was  supposed  to  arise  exclu- 
sively from  the  carbohydrate  radicle  in  protein,  but 
it  was  soon  shown  that  this  radicle  could  not  possibly 
account  for  the  amounts  of  glycogen  found  in  the 
tissues  of  experimental  animals. 

There  are  two  methods  of  approach  to  the  prob- 
lem: first,  the  direct  method.  In  this  method  an 
animal  is  rendered  glycogen  free  by  one  of  several 
means — starvation,  work,  or  strychnine  poisoning. 
Then,  after  a  suitable  period  during  which  but  one 
sort  of  food,  i.e.,  protein,  is  fed,  the  animal  is  killed 
and  the  glycogen  in  the  organs  quantitatively  esti- 
mated. If  the  glycogen  found  exceeds  that  of  control 
animals,  killed  after  starvation,  this  excess  must  have 
come  from  the  food  taken.  The  second  or  indirect 
method  depends  on  the  principle  that  foods  which 
form  sugar  are  indirect  glycogen  formers.  In  this 
method  animals  are  made  diabetic  either  with  phlor- 


14  DIABETES  MELLITUS 

hizin  or  by  removal  of  the  pancreas,  and  account  is 
taken  of  the  food  eaten  and  the  sugar  produced  (ex- 
creted). 

The  direct  method  was  used  by  Bernard.  He 
stated  that  glycogen  was  stored  in  the  liver  when 
only  flesh  was  taken,  and  from  this  observation  he 
argued  that  protein  can  be  transformed  in  the  animal 
body  into  glycogen.  Bernard  did  not  make  proper 
allowance  for  the  glycogen  in  flesh  eaten,  which  may 
be  as  much  as  one  per  cent. 

The  most  complete  researches  on  the  derivation  of 
glycogen  from  protein  as  tested  by  the  direct  method 
are  those  of  Kulz.7  This  investigator  in  his  work 
used  pigeons  and  hens.  It  was  observed  that  after 
two  to  four  days'  starvation  the  average  amount  of 
glycogen  in  the  liver  and  muscles  was  0.946  gramme 
per  kilo  body  weight,  and  that  after  four  to  eight  days' 
starvation  the  liver  became  glycogen  free  while  the 
muscle  glycogen  averaged  0.716  gramme  per  kilo 
body  weight,  with  1.414  as  a  maximum.  Kulz  used 
thirty-three  birds  in  establishing  his  averages.  The 
birds  were  fed  from  fifteen  to  twenty-five  days  on 
flesh  powder  which  had  been  extracted  until  glycogen 
free.  With  the  pigeons  the  glycogen  content  of  liver 
and  muscles  was  found  to  average  2.03  grammes  per 
kilo.    Subtracting  from  this  the  starvation  maximum 

T  Reported  by  Pfluger:  Arch.  f.  d.  ges.  Physiol.,  1903,  Bd.  96,  p.  1. 


GLUCOSE  IN  THE  ANIMAL  BODY  15 

(2.03  —  1.414),  the  positive  increase  amounts  to  only 
0.616  gramme.  This  is  a  small  amount,  and  it  is 
possible  to  account  for  it  in  traces  of  glycogen  in  the 
meat  too  small  to  give  reactions  in  tests  for  it,  since 
an  equivalent  of  5  kilos  of  fresh  flesh  was  fed.  Then, 
too,  a  slight  decomposition  in  the  meat  during  the 
process  of  extraction  would  convert  the  glycogen  into 
dextrin,  which  would  escape  detection  (Brucke-Kulz 
method).  From  these  researches  Pfliiger  concluded 
that  "  even  with  excessive  flesh  feeding  no  deposition 
of  glycogen  had  occurred." 

If  it  be  shown  that  glucose  may  take  origin  in  the 
animal  body  from  protein  the  glycogen  stores  are  ex- 
plained. The  solution  of  this  question  rests  largely 
on  experimental  diabetes.  It  is  owing  to  the  classical 
researches  of  Von  Mering  and  Minkowski  that  the  ex- 
perimental difficulties  surrounding  this  question  were 
overcome.  When  dogs  are  rendered  diabetic  by  re- 
moval of  the  pancreas  and  are  then  given  exclusively 
protein  food  the  amounts  of  sugar  excreted  in  the 
urine  are  much  too  large  to  be  accounted  for  by  any 
possible  glycogen  reserves  in  the  body.  The  urinary 
sugar  can  have  but  two  possible  sources,  the  proteins 
of  the  food  (and  tissues)  and  fat.  An  experiment  of 
Liithje  seems  to  demonstrate  this  point.8  A  dog 
weighing  5.8  kilos  during  twenty-five  days  after  re- 

•  Arch.  f.  d.  ges.  Physiol.,  1904,  cvi,  p.  160. 


16  DIABETES  MELLITUS 

moval  of  the  pancreas  excreted  1176  grammes  of 
dextrose  on  a  carbohydrate-free  diet.  According  to 
the  average  determined  by  Pfliiger  the  maximum 
amount  of  glycogen  the  dog's  body  might  have  con- 
tained would  be  232  grammes  (5.8  X  40)  but  this 
would  account  for  only  257  grammes  of  sugar,  leav- 
ing 919  grammes  (1176  —  257)  unaccounted  for. 
Von  Mering  noted  that  when  his  dogs  were  fed  on 
meat  and  fat  only,  after  the  first  three  or  four  days 
the  total  daily  excretion  of  sugar  and  nitrogen  bore  a 
constant  relation  to  each  other,  which  suggested  a 
common  origin  for  the  sugar  and  nitrogen.  This  re- 
lation varies  slightly,  but  in  completely  depancrea- 
tized  dogs  the  ratio  of  sugar  to  nitrogen  (D  :  N)  is 
from  2.9  : 1  to  3.05  : 1. 

The  large  sugar  excretion  which  is  observed  for 
the  first  two  or  three  days  after  the  removal  of  the 
pancreas  is  derived  from  the  glycogen  stores  in  the 
liver  and  muscles,  but  if  the  animals  be  killed  five  or 
six  days  after  the  operation  only  mere  traces  of  glyco- 
gen are  detectable  in  these  tissues,  and  this  is  so  no 
matter  whether  food  has  been  given  liberally  or  with- 
held.9 

It  is  evident,  then,  that  after  the  first  few  days  there 
are  but  two  possible  sources  for  the  sugar  excreted  by 

•Macleod:  Recent  Advances  in   Physiology  and  Biochemistry,  1906, 
p.  349. 


GLUCOSE  IN  THE  ANIMAL  BODY  17 

depancreatized  animals,  namely,  protein  and  fat.  It  is 
the  opinion  of  Minkowski  that  the  sugar  is  derived  ex- 
clusively from  protein.  If  the  carbon  in  protein  were 
converted  into  sugar,  100  grammes  of  protein  would 
yield  113  grammes  of  grape  sugar  and  16  grammes 
of  nitrogen.  This  would  mean  a  ratio  of  seven 
(D:N  =  7:1).  But  Minkowski's  ratio  is  three. 
Two  hypotheses  suggest  themselves  in  explanation: 
first,  all  the  carbon  in  protein  is  converted  into  sugar 
but  in  depancreatized  dogs  a  constant  part  of  this 
sugar  is  destroyed  in  the  body ;  second,  only  a  part  of 
the  carbon  in  protein  is  converted  into  sugar.  Min- 
kowski and  others  have  attempted  to  determine 
whether  animals  rendered  diabetic  by  complete  removal 
of  the  pancreas  are  able  to  utilize  any  dextrose.  It  was 
Minkowski's  decision  that  ingested  dextrose  is  en- 
tirely recoverable  in  the  urine.  Only  moderate 
amounts  can  be  given  in  this  way,  however,  since 
large  doses  cause  diarrhoea  preventing  absorption,  and 
when  the  small  dosage  is  used  it  is  difficult  to  determine 
an  increase  of  sugar  in  the  urine  because  of  the  normal 
fluctuation  of  the  sugar  excretion  in  depancreatized 
dogs.  Other  investigators,  however,  have  not  accepted 
Minkowski's  results,  but  have  concluded  that  the 
organism  still  retains,  after  pancreatectomy,  a  slight 
ability  to  destroy  dextrose ;  that  is,  all  the  administered 
dextrose  does  not  appear  in  the  urine,  although  the 


18  DIABETES  MELLITUS 

greater  part  of  it  does.10  It  is  believed  by  most  physi- 
ologists that  the  sugar  destroyed,  if  any,  is  of  a  negli- 
gible amount.  The  reasons  for  this  belief  are  based 
upon  the  respiratory  quotient  found  with  depancrea- 
tized  dogs.  This  quotient  is  so  low  that  only  protein 
and  fat  combustion  would  account  for  it.  If  no  sugar 
or  at  most  but  traces  of  sugar  are  burned,  then  the 
first  hypothesis  falls  and  we  are  forced  to  conclude 
that  only  a  part  of  the  carbon  in  protein  is  converted 
into  glucose.  The  possibility  suggested  by  Minkowski 
that  45  grammes  of  sugar  is  the  maximum  derivable 
from  100  grammes  of  protein  ( 100  grammes  -r-  6.25  = 
16  grammes  nitrogen.  16  X  2.8  =  44.8),  in  accord- 
ance with  the  D :  N  ratio  of  experimental  diabetes, 
rests  chiefly  on  the  respiratory  quotient.  The  salient 
fact  is  that  there  is  a  constant  relation  between  the 
nitrogen  and  sugar  output,  and  this  fact  is  the 
major  support  of  the  doctrine  of  the  origin  of  sugar 
from  protein.  Until  late  in  his  life,  Pfliiger,  the 
most  exacting  critic  in  this  field  of  investigation, 
denied  the  origin  of  sugar  from  protein.  He  be- 
lieved that  the  excess  of  excreted  dextrose  is  de- 
rived from  fat  and  advanced  a  complex  explanation 
which  is  now  only  of  an  historical  interest.  On  the 
basis  of  his  own  experiments  by  the  direct  method  of 

10  Langstein :  Ergebnisse  der  Physiologie,  1902,  Bioch.  Abth.,  p.  96; 
1904,  1st  Abth.,  p.  453. 


GLUCOSE  IN  THE  ANIMAL  BODY  19 

glycogen  accumulation  Pfliiger  convinced  himself  of 
the  formation  of  sugar  from  protein.  The  consensus 
of  opinion  at  present  accepts  this  transformation  as 
demonstrated. 

The  work  of  Emil  Fischer  has  disclosed  that 
proteins  are  aggregations  of  various  amino-acids 
linked  together,  and  we  know  that  in  process  of 
digestion  the  protein  molecule  is  split  up  by  trypsin 
into  its  simplest  components,  amino-acids  such  as  leu- 
cine, tyrosine,  alanine, etc.  The  question  arises: Which, 
if  any,  of  these  acids  are  sugar  formers?  Kossel  first 
called  attention  to  the  fact  that  some  of  these  amino- 
acids — leucine,  arginine,  lysin — contain  the  same  num- 
ber of  carbon  atoms  as  dextrose.  KosseFs  idea,11 
later  expressed  by  F.  Miiller,  was  that  protein  which 
yielded  so  much  amino-acid  could  hardly  contain  a 
sugar  radicle  equal  to  60  per  cent.,  the  inference  be- 
ing that  sugar  must  be  derived  from  some  of  these 
acids.  The  matter  was  first  submitted  to  experiment 
by  Knopf,12  who  gave  an  amino-acid,  asparagine,  to  a 
dog  partly  poisoned  with  phlorhizin,  and  observed  an 
appreciable  increase  in  the  amount  of  sugar  excreted. 
In  the  meantime  Lusk  13  demonstrated  that,  by  suit- 
able use  of  phlorhizin,  dogs  could  be  made  to  give  a 

n  Kossel:  Deutsch.  med.  Wochschr.,  1898,  xxiv,  p.  581. 

"  Knopf:  Arch.  f.  exper.  Path.  u.  Pharmakol.,  1903,  xlix,  p.  123. 

13  Lusk:  Zeitschr.  f.  Biol.,  1898,  xxxvi,  p.  82. 


20  DIABETES  MELLITUS 

D  :  N  ratio  of  3.65  : 1.  This  ratio,  higher  than  Min- 
kowski's, would  indicate  even  less  utilization  of  glucose 
in  the  dog  poisoned  with  phlorhizin  than  is  the  case  in 
the  dog  whose  pancreas  is  removed.  Since  the  opera- 
tion of  complete  removal  of  the  pancreas  is  a  difficult 
one,  this  discovery  of  Lusk  was  important,  and  the 
method  he  devised  has  yielded  very  interesting  results. 
For  a  number  of  amino-acids  the  data  at  hand  point 
to  the  conclusion  that  they  are  dextrose  formers.  This 
is  the  case  with  glycocoll,  alanine,  aspartic  and  glutamic 
acids,  to  mention  some  of  the  more  important  acids.14 
The  investigations  of  Embden  and  Salomon,15  Baer 
and  Blum,16  and  Glaessner  and  Pick,17  antedated  some 
of  Lusk's  work  but  none  of  their  investigations  was  con- 
clusive since  in  all,  the  animals  were  but  partly  diabetic. 
Of  no  less  interest  is  the  observation  that  leucine  18  and 
tyrosine  19  do  not  undergo  transformation  into  dex- 
trose. 

The  metabolism  of  leucine  and  tyrosine  and  the 

"Lusk:  Zeitschr.  f.  physiologische  Chemie,  1910,  66>  p.  115;  Ergeb. 
f.  Physiol.,  1912,  loc.  cit. 

10  Embden  and  Salomon:  Beitr.  z.  chem.  Physiol,  u.  Path.,  1904,  v, 
507;   vi,   p.   63. 

"Baer  and  Blum:  idem,  1907,  x,  pp.  80-104. 

"Glaessner  and  Pick:  idem,   1907,  x,  p.  473. 

"  Embden,  Salomon  and  Schmidt:  Beitr.  z.  chem.  Physiol,  u.  Path., 
1906,  vni,  pp.  121-156.  Baer  and  Blum:  Arch.  f.  exp.  Pathol,  u.  Pharm., 
1906,  55)  pp.  89-111. 

18  Lusk :  vide  supra. 


GLUCOSE  IN  THE  ANIMAL  BODY  21 

formation  from  them  of  £-oxybutric  acid  will  be  dis- 
cussed in  another  section. 

It  would  be  of  considerable  interest  to  have  knowl- 
edge of  the  intermediary  substances  through  which  an 
amino-acid  must  pass  on  its  way  to  glucose.  The  data 
at  command  allow  only  inferences.  Some  clue  to  the 
possible  course  of  events  was  given  by  the  observation 
(Neuberg)  that,  after  the  ingestion  of  alanine,  lactic 
acid  appears  in  the  urine  of  rabbits,20  while  glycogen 
is  deposited  in  the  liver.  It  has  also  been  shown  that  in 
diabetic  dogs  d-lactic  acid 21  is  completely  converted 
into  dextrose.  The  chemical  change  required  for  the 
transformation  of  alanine  to  lactic  acid  is  an  easy  step 
and  one  in  accord  with  other  known  transformations — 


CH3 

I 

CH3 

CH-NH2+H20     = 

=    CHOH 

1 

CO-OH 

Alanine 

COOH 

Lactic  acid 

The  substitution  of  an  hydroxyl  ( OH )  group  for  an 
amino  (NH2)  group  (deamidization)  is  a  process  met 
with  frequently  in  animal  chemistry. 

It  is  more  difficult  to  explain  the  origin  of  sugar 
from  lactic  acid.  All  one  may  do  at  this  time  is  to 
state  the  hypotheses  that  have  been  advanced  in  ex- 
planation, but  for  which  substantial  basis  is  still  lack- 

30  Neuberg:  Arch.  f.  Physiol,  u.  Pathol.,  1908,  p.  473. 
"Mandel  and  Lusk:  Am.  Jour.  Physiol.,  1906,  xvi,  p.  129. 


22  DIABETES  MELLITUS 

ing.  One  conception  (Stoklasa22)  is  that  the  lactic 
acid  is  broken  up  into  alcohol  and  CO-2.  This  can 
scarcely  be  the  case  since  alcohol  is  not  a  sugar  former 
in  human  or  experimental  diabetes.  According  to 
another  hypothesis  lactic  acid  is  transformed  into 
glyceric  aldehyde  with  methylglyoxal  as  an  inter- 
mediary product  (Wohl 23)  while  Lob 24  believes  that 


COOH       COH   CH2OH 

1                 1 

CH2OH 

1 

CHOH^>  CO-»  CHOH  -> 

1           | 

CHOH 

1 

CH,           CH3     CHO 

Lactic  acid    Methyl  Glycerose 
glyoxal 

CHOH 

1 
CHOH 

CHOH 

CHO 

even  simpler  substances  than  lactic  acid  are  the  build- 
ing stones  of  glucose,  namely,  that  the  lactic  acid 
goes  to  form  acetol  and  this  last  in  turn  to  formalde- 
hyde from  which  glucose  is  constructed.  This  idea 
would  bring  animal  and  plant  physiology  in  accord 
since  it  is  believed  that  formaldehyde  is  the  basis  for 
sugar  production  in  plants  (Baeyer's  hypothesis) .  It 
is  not  probable  that  sugar  formation  from  amino-acids 
takes  place  through  lactic  acid  in  all  cases.  At  least 
such  a  transformation  would  seem  indirect  from  a 
purely  chemical  standpoint.    For  example,  glutamic 

22  Stoklasa:  Beitr.  z.  chem.  Physiol,  u.  Pathol.,  1903,  3,  p.  60. 
"Biochem.  Zeitschr.,  1907,  v,  p.  45. 
"Lob:  Biochem.  Zeitschr.,  1908,  xn,  p.  78. 


GLUCOSE  IN  THE  ANIMAL  BODY 


23 


acid,  following  known  laws,  would  break  at  the  ^-car- 
bon atom,  glyceric  and  acetic  acids  resulting — 

COOH  COOH 

i  |  COH 

CH2  CH3 

CHOH 

I 
CH2OH 


8CH2+2H20  =  CH2OH 

I                        I 
CHNH2  CHOH  >   Glycerol 

I  I 

COOH  COOH 

Glyceric  acid 

and  from  the  glyceric  acid  to  glucose  is  an  easy  step. 
Positive  knowledge  in  this  field  of  bio-chemistry  is 
so  deficient  that  no  conclusion  can  be  made  and  we 
must  be  content  for  the  present  in  stating  the  general 
principles  which  seem  to  apply  to  various  possible 
processes.  A  mere  comparison  of  several  substances 
recalling  to  mind  the  ease  with  which  ammonia  groups 
are  added  or  abstracted  is  sufficient  to  indicate  the 
many  possibilities : 


CH, 

I 

CHOH 

I 
COOH 

Lactic  acid 


CH3 

I 

CHNH2 

I 
COOH 

Alanine 
(amino- 
propionic 
acid) 


CH2SH 

I 
CHNH2 

! 

COOH 

Cystine 

(a-amino- 

|3-thio 


CH2OH 

I 
CHNH2 

I 
COOH 

Serine 

(a-amino- 

/3-hydroxy 


propionic  acid)  propionic  acid) 


CHO 

I 
CHOH 

I 
CH2OH 

Glycerose 

(glyceral 

aldehyde) 


CH2OH 

I 
CHOH 

I 
CH2OH 

Glycerol 


Formation  of  Sugar  from  Fat. — While  the  forma- 
tion of  fat  from  sugar  is  one  of  the  best  attested  facts  in 
physiology  the  reverse  process  as  applying  to  animals 
has  been  the  source  of  no  little  dispute.  One  of  the 
earliest  observations  relating  to  the  change  of  one  food 
stuff  into  another  was  on  the  fat  formation  in  ripening 


24  DIABETES  MELLITUS 

seeds.  We  know  that,  while  unripe  seeds  contain  large 
amounts  of  carbohydrate  and  but  mere  traces  of 
fat,  the  ripened  seed  contains  much  fat  and  but  little 
carbohydrate.  How  definite  this  change  is,  is  shown 
by  the  following  analyses  of  nuts  by  du  Sablon.25 
The  figures  are  parts  per  100. 

Oil    Glucose 

July   6    3  7.6 

August  1    16  2.4 

September  1    59  0 

October  4 62  0 

We  also  know  that  during  the  germination  of  seeds 
the  fat  gradually  disappears  while  carbohydrates  take 
their  place;  that  is,  the  process  is  reversed.  There  is 
no  doubt,  then,  in  so  far  as  plants  are  concerned,  of  the 
transformation  of  fat  into  carbohydrate.  With 
animals  we  are  nearly  convinced  that  ingested  carbo- 
hydrate in  excess  of  demand  is  in  part  stored  as  fat. 
The  difficulty  lies  in  the  reversal  of  the  process.  At 
once  it  may  be  conceded  that  there  is  no  more  difficulty 
in  its  chemical  aspect  in  understanding  the  transforma- 
tion of  fat  into  sugar  than  the  origin  of  sugar  from 
protein.  Moreover,  it  is  argued  by  the  advocates  of 
this  theory  that  the  process  involved  is  one  dependent 
on  enzyme  activity  and  enzymes  are  reversible  in  their 
action.  In  the  first  place  it  is  difficult  to  conceive  why 
this  process  is  necessary  since,  so  far  as  anything  is 
known,  the  muscles  might  use  fat  directly  as  a  source  of 

36  Compt.  rend.,  1896,  123,  p.  1084. 


GLUCOSE  IN  THE  ANIMAL  BODY  25 

energy,  and  according  to  Zunzt  the  transformation  of 
fat  into  sugar  before  combustion  would  entail  a  loss 
in  energy  of  nearly  30  per  cent.  The  methods  em- 
ployed in  the  investigation  of  this  question  are  the 
same  as  those  used  for  the  determination  of  the  origin 
of  carbohydrate  from  protein:  namely,  the  direct, 
depending  on  storage  of  glycogen,  and  the  indirect, 
depending  on  the  sugar  excreted  in  diabetic  animals. 
It  is  now  a  matter  of  common  observation  that  an 
increase  of  fat  in  the  diet  of  a  diabetic  subject  does  not 
increase  the  amount  of  sugar  excreted  in  the  urine. 
The  observation  of  Hiibner  illustrates  this  point  in  a 
diabetic  patient.  The  albumen  of  the  diet  was  de- 
creased and  at  the  same  time  the  fat  was  increased. 
The  sugar  excretion  fell  with  the  diminished  protein 
ingest. 

176  gms.  albumen  +  150  gms.  fat  =  urine-sugar,  51  gms. 

176  gms.  albumen  +  319  gms.  fat  =  urine-sugar,  50  gms. 

98  gms.  albumen  -f-  315  gms.  fat  =  urine-sugar,     7  gms. 

The  fact  that  the  ingestion  of  large  amounts  of  fat 
does  not  increase  the  urinary  sugar  is  attested  by 
numerous  experiments  and  the  daily  practice  of  physi- 
cians who  treat  diabetic  patients.  But  when  we  ex- 
amine this  evidence  it  proves  nothing  in  so  far  as  the 
question  of  the  origin  of  carbohydrate  from  fat,  and 
for  this  reason:  food  substances  are  utilized  by  the 
animal  organism  with  varying  degrees  of  facility. 

For  heat  and  energy  carbohydrates  are  burned  first, 
3 


26  DIABETES  MELLITUS 

they  are  the  fuel  of  preference,  and  so  long  as  carbo- 
hydrate is  available,  be  it  circulating  sugar  or  stored 
glycogen,  there  will  be  little  demand  on  other  food 
materials.  When  the  carbohydrates  are  lacking — 
deprivation  in  food  or  depletion  of  glycogen  stores — 
the  proteins  are  next  attacked  as  a  source  of  energy. 
The  fats  remain  chiefly  a  last  reserve  material.  Thus 
it  becomes  evident  that  a  surplus  of  fat  in  the  diet 
does  not  of  necessity  enter  into  metabolism  but  is 
stored  as  fat  in  the  tissues.  However  much  fat  be  in- 
gested, it  will  not  be  consumed  for  energy  unless  the 
other  sources  of  heat  are  deficient.  This  is  sufficient 
to  explain  why  Hiibner's  results  are  not  so  vital  as 
they  at  first  seem.  As  Pfluger  put  it:  "  The  extent 
of  protein  metabolism  is  dependent  on  the  protein 
supply;  while  fat  metabolism  is  independent  of  the 
fat  supply."  26 

Voit  was  able  to  demonstrate  that  fat  metabolism 
ceased  as  soon  as  a  sufficient  supply  of  protein  be  fed. 
This  explanation  suffices  to  show  why  the  negative 
results  of  Hubner  afford  inadequate  evidence  against 
the  possible  origin  of  sugar  from  fat. 

Fat  is  a  compound  of  glycerol  and  fatty  acids, 
and  the  relation  that  each  of  these  substances  bears  to 
sugar  formation  must  be  separately  examined.  That 
glycerol  can  lead  to  sugar  formation  has  been  shown 

20  PflUger:  Das  Glycogen  u.  s.  w.,  p.  223. 


GLUCOSE  IN  THE  ANIMAL  BODY  27 

even  more  conclusively  than  sugar  formation  from 
protein.  This  happens  because  glycerol  can  be  fed  to 
animals  in  extremely  large  doses.  The  very  marked 
increase  in  sugar  excretion  which  follows  on  the  in- 
gestion of  glycerol  has  been  proved  for  human  (Kulz) 
and  experimental  (Liithje)  diabetes.27  But  it  is  not 
believed  that  neutral  fats  necessarily  undergo  a 
saponification  into  fatty  acids  and  glycerol  prior  to 
metabolism. 

We  may  now  ask :  On  what  evidence  does  the 
hypothesis  rest  that  fat  may  give  origin  to  sugar  in  the 
animal  body?  We  have  noted  that  there  is  no  a  priori 
reason  why  this  should  not  be  the  case.  The  theory 
owes  its  first  impetus  to  the  support  of  Pfliiger,  who 
never  abandoned  it.  The  adherents  of  the  doctrine  at 
present  offer  in  its  support  the  unaccountably  high 
D  :  N  ratios  which  have  occasionally  been  observed  in 
both  experimental  and  human  diabetes ;  ratios  of  glu- 
cose to  nitrogen  of  eight,  or  of  even  twelve,  are  on 
record.  If  all  the  carbon  in  protein  were  convertible 
into  carbohydrate,  100  grammes  of  protein  would  pro- 
duce 135  grammes  of  sugar  (100  grammes  protein, 
16  grammes  nitrogen) ,  which  would  be  equivalent  to  a 
D  :  N  ratio  of  eight.  It  is  quite  certain  that  so  much 
sugar  is  not  yielded  by  protein.    But  it  is  not  demon- 

"  Of  interest  here  are  the  experiments  of  Fischer  in  producing  a 
simple  sugar,  triose,  from  glycerol. 


28  DIABETES  MELLITUS 

strated  what  percentage  is  the  maximum  yield;  there 
are  differences  of  opinion  which  indicate  always  that 
the  results  of  experiments  are  equivocal.  Now  it  is 
quite  evident  that  until  it  is  known  what  is  the  amount 
of  available  sugar  from  protein — what  is  the  highest 
D  :  N  ratio — this  ratio  is  a  broken  reed  as  a  support 
to  an  hypothesis.  On  the  other  hand,  in  some  of  the 
observations,  at  least  where  high  ratios  have  been 
found  in  human  diabetes,  sufficient  deduction  for  in- 
gested carbohydrate  has  not  been  made.  The  investi- 
gators have  been  deceived. 

In  experiments  with  animals  where  a  ratio  higher 
than  3.6  has  been  observed  it  has  been  always  easy  to 
find  some  possible  error  in  the  mode  of  conduction  of 
the  experiment.  In  both  experimental  pancreatic  and 
phlorhizin  diabetes  a  standard  procedure  has  been 
worked  out  by  Minkowski  and  by  Lusk,  and  if  the 
conditions  these  experimenters  have  adopted  are  not 
fulfilled  almost  any  ratio  is  possible.  In  pancreatic 
diabetes  the  pancreas  must  be  completely  removed — 
it  is  not  safe  to  leave  a  vestige  of  tissue  if  Minkowski's 
ratio  of  2.8  is  to  be  attained.  With  phlorhizin  dia- 
betes the  drug  must  be  given  frequently  and  the  animal 
must  be  rendered  glycogen-free  by  exposure  to  cold. 
Lusk  has  found  that  all  preparations  of  phlorhizin  are 
not  equally  trustworthy.  When  these  conditions  are 
fulfilled  the  ratios  have  usually  been  secured.    With 


GLUCOSE  IN  THE  ANIMAL  BODY  29 

depancreatized  dogs  Minkowski  found  2.8,  while  Lusk, 
in  dogs  completely  freed  of  glycogen,  by  means  of 
phlorhizin  secured  a  ratio  of  3.6.  Magnus-Levy  be- 
lieves the  latter  figure  represents  the  maximal  sugar 
production  corresponding  to  one  gramme  of  nitrogen. 
The  respiratory  quotient  found  with  completely 
phlorhizinized  dogs  indicates  that  no  carbohydrate  is 
being  burned,  which  is  strong  evidence  in  favor  of 
Lusk's  ratio  of  3.65. 

The  condition  of  affairs  in  human  diabetes,  in  re- 
gard to  the  origin  of  the  excreted  carbohydrate,  may  be 
the  same  as  in  experimental  animals  and  is  usually 
assumed  to  be  so.  The  metabolism  in  human  dia- 
betes may,  however,  be  different,  for  anything  known 
to  the  contrary,  from  that  of  the  experimental  dis- 
ease. To  throw  any  light  upon  the  question  of  the 
origin  of  sugar  from  fat  only  the  severest  types  of 
human  diabetes  are  of  use  for  study,  since  the  others 
retain  considerable  ability  to  utilize  carbohydrate. 
Even  with  the  severe  cases  where  death  results  from 
coma,  the  organs  frequently  contain  some  glycogen, 
and  it  would  be  quite  impossible  to  assert  that  excess 
of  urinary  sugar  over  the  theoretical  amount  arising 
from  protein  had  not  come  from  glycogen  rather  than 
fat  unless  a  most  rigid  diet  be  adhered  to  for  a  con- 
siderable period.  The  author  has  had  occasion  to 
study  several  diabetic  patients  where  the  ratio  of 


30  DIABETES  MELLITUS 

sugar  to  nitrogen  excretion  appeared  at  first  to  be 
over  3.6,  but  in  every  instance  a  strict  control  of  the 
diet  by  competent  special  nurses  has  resulted  after  a 
day  or  two  in  a  fall  of  sugar  excretion  to  a  3.6  ratio.28 
Until  we  know  with  the  highest  exactness  what  the 
maximal  ratio  may  be — in  other  words  until  it  is 
known  what  is  the  largest  amount  of  sugar  attributable 
to  protein — it  does  not  seem  probable  that  we  will  be 
able  to  learn  whether  fat  may  yield  a  slight  amount  of 
sugar.  The  diabetic  patient  is  for  several  reasons  an 
extremely  difficult  subject  for  these  experiments.  It 
is  usually  impossible  to  restrict  him  for  a  period  of  a 
week  to  a  fat-protein  diet,  hence  we  cannot  be  sure 
that  he  is  not  eliminating  as  glucose  previously  stored 
glycogen.  This  rules  out  those  cases  where  carbo- 
hydrates have  been  fed  in  known  amounts.  Again, 
only  under  the  conditions  of  a  most  carefully  con- 
ducted experiment  can  the  possibility  of  nitrogen  re- 
tention be  excluded. 

The  complexity  of  the  question  is  evident  from 
this  cursory  summary,  and  it  is  sufficient  to  say  at 
present  that  the  problem  of  the  formation  of  sugar 
from  fat  has  not  been  substantiated.  Endeavors 
have  been  made  to  support  the  thesis  of  the  origin  of 
sugar  in  fat  by  respiration  calorimetric  experiments, 

**  Mendel  and   Lusk:   Deut.   Arch.    f.   klin.   Med.,   1904,   81,  p.   472. 
Foster:  Deut.  Arch.  f.  klin.  Med.,  1913. 


GLUCOSE  IN  THE  ANIMAL  BODY  31 

but  with  no  convincing  result.29  A  discussion  of  these 
experiments  will  be  considered  under  the  subject  of 
respiratory  quotients. 

If  fat  can  be  transformed  at  all  into  sugar  it  must 
be  only  in  the  most  insignificant  amounts,  and  this 
statement  is  abundantly  substantiated  by  a  crucial 
experiment  of  Lusk.30  If  sugar  can  be  derived  from 
fat  then  those  conditions  which  increase  the  catabol- 
ism  of  fat  would  increase  the  production  of  glucose. 
Using  dogs  completely  under  the  influence  of  phlor- 
hizin,  Lusk  induced  an  increase  of  60  per  cent,  in  the 
fat  catabolism  by  exposure  to  cold  in  one  set  of  ex- 
periments, and  in  another  series  by  mechanical  work 
the  fat  catabolism  was  doubled  without  in  either  case 
increasing  urinary  glucose  over  that  derived  from  pro- 
tein. 

These  experiments  refute  decisively  the  theory  of 
Von  Noorden  that  appreciable  amounts  of  sugar  re- 
sult from  fat  catabolism. 

A  large  part  of  the  energy  required  by  the  body 
is  derived  from  carbohydrates  and  some  considera- 
tion of  the  possible  ways  in  which  this  energy  is  de- 
veloped remains  to  be  mentioned.  All  carbohydrates 
are  converted  into  simple  sugars  before  combustion  in 
the  tissues.    The  possible  modes  of  oxidation  of  glu- 

29  Grafe  u.  Wolf:  Deut.  Arch.  f.  klin.  Med.,  1912,  cxvn,  p.  201. 
"Amer.  Jour.  Physiol.,  1908,  22,  p.  162. 


32 


DIABETES  MELLITUS 


cose  must  conform  to  the  known  facts  that  the  end 
products  are  carbon  dioxide  and  water,  and  that  by 
the  combustion  about  four  calories  are  developed  for 
each  gramme  of  glucose  burned.  This  oxidation  prob- 
ably takes  place  through  a  number  of  stages,  and, 
because  relatively  too  small  amounts  for  detection  of 
any  substance  resulting  from  the  cleavage  are  present 
at  any  one  moment,  our  knowledge  of  these  stages  is 
neither  clear  nor  exact.  Based  upon  the  reactions 
which  take  place  in  vitro  when  glucose  is  subjected  to 
oxidizing  reagents,  and  upon  the  analogy  with  fer- 
mentation, various  hypotheses  have  been  advanced  to 
account  for  the  combustion  in  the  tissues.  According 
to  these  hypotheses  this  combustion  may  be  classed  as 
direct  and  indirect  oxidation. 

In  direct  oxidation  glucose  might  involve  oxalic 
acid,  ^-glucuronic,  ^-gluconic,  or  <Z-saccharic  acid. 


d-glucose 

d-glucuronic 

d-gluconic 

d-saccharic 

COH 

COH 

COOH 

COOH 

1 

1 

\ 

\ 

H-C-0  H 

HCOH 

HCOH 

HCOH 

\ 

\ 

\ 

\ 

H  O-C-H 

HOCH 

HOCH 

HOCH 

/ 

/ 

/ 

/ 

HCOH 

i 

HCOH 

1 

HCOH 

1 

HCOH 

1 

HCOH 

1 

HCOH 

1 

HCOH 

i 

HCOH 

CH2OH 

COOH 

CH2OH 

COOH 

It  is  generally  considered  that  oxalic  acid  cannot  be  a 
normal  step  in  glucose  oxidation  in  the  body.  Neither 
gluconic  nor  saccharic  acids  have  been  found  in  ani- 


GLUCOSE  IN  THE  ANIMAL  BODY  33 

mal  tissues  and  they  do  not  behave  in  the  body  in  a  way 
that  supports  the  hypothesis  that  the  normal  oxida- 
tion of  glucose  proceeds  through  these  steps.  The 
fact  that  they  are  burned  in  the  diabetic  organisms 
does  not  of  necessity  argue  against  this  hypothesis, 
however,  since  it  might  lie  in  the  initial  step  that  the 
diabetic  organism  meets  its  difficulty.  These  state- 
ments do  not  apply  to  glucuronic  acid,  as  this  acid 
occurs  in  normal  urine  and  there  seems  no  question 
of  its  derivation  from  glucose.  The  amounts  in  the 
urine  may  be  increased  by  the  administration  of  drugs 
such  as  camphor  and,  notably,  by  thymotin-piperidid. 
Animals  may  be  protected  from  lethal  doses  of  the 
latter  by  giving  large  amounts  of  carbohydrate 
foods.31  The  question  at  issue  is  whether  glucuronic 
acid  is  a  normal  intermediary  product  in  sugar  com- 
bustion combining  in  the  organism  with  substances 
like  camphor,  or  whether  these  drugs  in  some  way 
pervert  the  normal  course  of  catabolism  to  the  forma- 
tion of  glucuronic  acid.  No  definite  answer  can  be 
given  to  this  question  at  present. 

Another  conception  of  the  mode  of  carbohydrate 
combustion  in  the  body  is  based  upon  the  analogy  of 
alcoholic  fermentation.  In  the  transformations  that 
occur  in  the  process  of  alcoholic  fermentation  it  is 
known  that  lactic  acid  is  found  as  an  intermediary 

a  Mayer:  Zeit.  f.  physiol.  Chem.,  1900,  26,  p.  256. 


34 


DIABETES  MELLITUS 


step,  and  probably  methylglyoxal  also.  A  basis  for 
the  hypothesis  lies  in  the  fact  that  from  acetol  lactic 
acid  is  derivable  with  methylglyoxal  as  the  inter- 
mediary substance.  Applying  these  considerations  to 
the  cleavage  of  glucose  in  the  body,  f  ormuke  might  be 
written  as  follows : 


Glucose 

CHO 

1 

X 

COOH 

1 

Methyl- 
glyoxal 

COH 

I 

Lactic 
acid 

COOH 

1 

CQ2 

CHOH 

CHOH 

1 

1 
CO 

1 

CHOH 

CH2OH  (alcohol) 

CHOH 

CHj 

I 

CH, 

CH, 

CH, 

CHOH 

1 

I 
CO 

1 

COH 

1 

COOH 

1 

CH2OH 

i 

CHOH 

i 

CHOH 

1 

1 
CO 

1 

CHOH 

l 

1 
CH, 

CH2OH 

CH2 

1 
CH, 

1 
CH, 

CO, 

This  scheme  requires  the  interpolation  of  a  formula 
between  glucose  and  glyoxal  which  is  purely  hypo- 
thetical. For  the  rest  the  transformations  occur  with 
ease  and  in  accord  with  known  chemical  processes. 
The  evidence  deduced  by  muscle  analyses  in  sup- 
port of  this  theory  is  none  too  strong,32  however. 
Lactic  acid  is  found  in  muscle,  especially  after  exer- 
cise, and  the  amounts  recoverable  after  autolysis  of 
muscle  are  so  large  as  to  make  the  derivation  from 
glucose  most  probable.33  Ethyl  alcohol  has  also  been 
detected  in  muscle  but  only  in  traces. 

At  the  present  time  we  must  confess  that  we  are 

°  Asher  and  Jackson:  Zeitsch.  f.  Biol.,  1901,  41,  p.  393. 
"Magnus-Levy:  Beitr.  z.  chem.  Physiol,  u.  Pathol.,  1902,  2,  p.  261. 


GLUCOSE  IN  THE  ANIMAL  BODY  35 

quite  without  sufficient  data  to  form  any  clear  concep- 
tion of  the  breakdown  of  the  glucose  molecule,  and  it 
is  probable  in  the  initial  step  in  the  destruction  of 
glucose  that  the  essential  deviation  of  the  diabetic  from 
the  normal  becomes  manifest.  Certainly  the  dia- 
betic organism  is  usually  able  to  handle  the  cleavage 
products  of  glucose.  The  inability  to  effect  the  first 
cleavage  might  rest  in  a  change  in  the  cell  where  oxi- 
dation is  effected  or  in  the  absence  of  an  activator. 
In  the  light  of  our  knowledge  of  other  vital  processes 
we  must  assume  the  dependence  of  these  changes  upon 
zymases  elaborated  in  one  class  of  cells,  perhaps  the 
muscle,  and  in  order  to  effect  their  function  probably 
requiring  an  activator  or  hormone  secreted  perhaps 
by  quite  remote  and  different  cells. 


Ill 

EXPERIMENTAL  GLYCOSURIA 

The  production  of  glycosuria  in  animals,  while  it 
has  not  completely  solved  the  questions  of  the  etio- 
logical factors  in  human  diabetes,  has,  however,  served 
a  most  important  purpose  in  enabling  physiologists  to 
gain  some  insight  into  normal  carbohydrate  metab- 
olism and  the  various  influences  that  control  this 
function.  Chronologically,  the  "  puncture  diabetes  ' 
or  piqure  discovered  by  Claude  Bernard  is  the  oldest 
method  we  have  of  inducing  glycosuria.  Bernard 
noted  that  if  a  needle  be  inserted  into  the  medulla  at 
the  inferior  part  of  the  calamus  scriptorius  there  en- 
sues an  excretion  of  sugar  in  the  urine.  This  glyco- 
suria persists  for  a  variable  length  of  time,  commonly 
several  hours.  It  was  further  observed  by  Bernard 
that  glycosuria  follows  piqure  only  when  the  animals 
are  in  a  normal  state  of  nutrition;  and  that  it  is  en- 
tirely inhibited  by  fasting  for  a  suitable  period  pre- 
vious to  the  experiment.  The  meaning  of  this  is  ex- 
plained by  the  fact  that  starvation  frees  the  liver  of 
its  glycogen.  There  is  no  consequent  glucose  excre- 
tion unless  the  liver  contain  glycogen.  Following 
puncture  the  blood  sugar  increases.     Piqure  glyco- 

36 


EXPERIMENTAL  GLYCOSURIA  37 

suria  is  then  an  example  of  increased  glycogenolytic 
function  in  the  liver.  Some  of  the  nervous  mechan- 
isms which  influence  this  form  of  melituria  were  re- 
markably well  shown  by  Bernard's  investigations.1 
It  was  noted,  for  example,  that  division  of  the  vagi 
did  not  prevent  the  glycosuria  due  to  piqure  and  that 
stimulation  of  the  peripheral  stump  of  the  vagus  had 
no  effect.  Stimulation  of  the  central  stump,  however, 
induces  glycosuria.  Bernard  observed  that  the  livers 
of  experimental  animals  showed  hyperemia  and  he 
conjectured  that  the  nervous  influence  operated  in 
some  way  through  the  circulation.  The  researches  of 
Eckhard  2  made  it  clearer  that  the  medulla  acts  as  a 
reflex  centre  in  the  production  of  this  form  of  gly- 
cosuria. Stimulation  of  any  afferent  nerve  fibre  will 
cause  transitory  glycosuria.  This  has  been  shown  best 
with  the  vagus.  If  the  central  stump  be  left  acces- 
sible after  the  nerve  is  divided  Eckhard  demonstrated 
that  electrical  stimulation  will  cause  a  transitory  gly- 
cosuria even  several  days  after  the  nerve  has  been 
divided.  It  is  requisite  in  this  case  as  with  piqure 
glycosuria  that  the  animals  be  well  fed.  Sugar  may 
be  caused  to  appear  in  the  urine  independent  of  punc- 

1  Cl.   Bernard:  Lecons  sur  le  Diabete  et  la  Glycogenese  animate, 
pp.  375-380.    Paris,  1877. 

'Eckhard:  Beitr.  z.  Anatomie  u.  Physiol.,  1869,  iv,  p.  4. 


38  DIABETES  MELLITUS 

ture  of  the  medulla  by  cutting  the  lower  cervical  or 
upper  thoracic  sympathetic  ganglia.3 

It  is  next  of  importance  to  consider  the  efferent 
impulses  from  the  medulla  and  whether  these  impulses 
concern  the  liver  glycogen  only.  In  this  relation  it 
has  been  commonly  stated  that  either  ( 1 )  cutting  the 
splanchnic  nerves  at  their  entry  into  the  abdomen, 
(2)  section  of  the  spinal  cord  above  the  first  thoracic 
root,  or  (3)  division  of  the  upper  three  thoracic  nerve 
roots,  prevents  the  glycosuria  4  resulting  from  piqure. 
These  observations  have  been  taken  to  mean  that  the 
path  for  the  efferent  impulses  from  the  "diabetic 
centre  "  in  the  medulla  is  by  the  cord  as  far  as  the 
upper  thoracic  region,  then  by  the  spinal  roots  and 
rami-communicantes  in  the  lower  cervical  or  superior 
sympathetic  ganglion.  As  glycosuria  usually  follows 
stimulation  of  the  great  splanchnic  nerve  but  is  pre- 
vented by  division  of  all  the  nerve  fibres  leading  to  the 
liver,  Pfliiger  believed  the  glycogenolysis  to  be  a  re- 
sult of  nerve  stimulation.  That  the  problem  might 
not  be  so  simple  of  solution  was  suggested  in  the  work 
of  Mayer,5  who  failed  to  secure  piqure  glycosuria  when 

8Schiff:  Untersuchung  iiber  die  Zuckerbildung  in  der  Leber  u,  den 
Einfluss  des  Nervensystems  auf  die  Erzeugung  des  Diabetes.  Wurzburg, 
1859. 

4  Eckhard:  loc.cit.  Laffont,  cited  by  Pfliiger:  Arch.  f.  d.  ges.  Physiol., 
1903,  96,  p.  1. 

•Mayer:  Compt.  rend.  Soc.  Biol.,  1908,  60,  p.  1123.  Kahn:  Pfliiger's 
Arch.,   1909,  pp.   128,  519. 


EXPERIMENTAL  GLYCOSURIA  39 

the  adrenals  had  been  removed  from  dogs  and  rabbits ; 
and  it  has  also  been  reported  that  stimulation  of  the 
splanchnic  nerves  fails  to  elicit  glucose  excretion  if 
the  adrenal  glands  are  previously  removed  from  the 
animal.6  Many  of  these  experiments  have  been  re- 
peated and  elaborated  by  Macleod7  and  his  pupils, 
with  the  conclusion  that  removal  of  the  adrenals  pre- 
vents the  hyperglycogenolysis  which  ordinarily  results 
from  stimulation  of  the  great  splanchnic  nerve.  This 
fact  does  not  indicate,  however,  that  the  secretion  of  the 
adrenals  is  the  direct  cause  of  the  hyperglycemia, 
since,  with  complete  section  of  the  hepatic  plexus, 
splanchnic  stimulation  is  not  usually  followed  by  hy- 
perglycemia. Still,  the  adrenals  seem  to  be  requisite 
for  the  production  of  hyperglycemia  and  glycosuria 
as  their  removal  effectually  prevents  the  usual  glucose 
excretion  following  on  stimulation  of  the  hepatic 
plexus.  Some  of  the  difficulties  in  interpreting  the 
results  of  these  experiments  will  be  cleared  away  as 
we  proceed.  It  has  been  attempted  to  explain  piqure 
and  neurogenous  glycosuria  by  supposing  the  enzymes 
governing  glycogenolysis  in  the  liver  are  under  ner- 
vous control.  An  attempt  to  measure  the  ferment 
content  of  the  liver  before  and  after  piqure  brought 

•Gautrelet  and  Thomas:  Compt.  rend.  Soc.  Biol.,  1909,  67,  p.  233. 
T  Macleod  and  Pearce:  Amer.  Jour.  Physiol.,  1912,  29,  p.  419. 


40  DIABETES  MELLITUS 

forth  no  convincing  differences  8  because  the  activity 
of  an  enzyme  depends  not  alone  on  its  quantity  but  also 
upon  the  conditions  (acid,  etc.)  under  which  a  con- 
stant amount  of  ferment  is  acting.9 

In  the  experiments  that  have  been  already  out- 
lined the  idea  has  usually  prevailed  that  the  stimulat- 
ing impulse  must  proceed  centrifugally  in  order  to 
produce  the  result  observed — glycogenolysis  and  gly- 
cosuria. As  a  rule  no  special  caution  has  been  exercised 
to  the  end  of  blocking  centripetal  stimuli.  The  fail- 
ure to  consider  this  possibility  explains  some  of  the 
discrepancies  in  results.  If  the  spinal  cord  and  both 
vago-sympathetic  trunks  are  divided,  all  nerve  con- 
nections to  abdominal  viscera  are  interrupted.  Under 
these  conditions  stimulation  of  the  cervical  sympa- 
thetic ganglion  induces  glycosuria.  Likewise  the  same 
form  of  10  stimulation  induces  glucose  excretion  when 
the  cord  is  cut  and  the  animal  poisoned  with  nicotine. 
If  the  posterior  lobe  of  the  hypophysis  (pars  nervosa) 
has  been  removed  there  is  no  melituria  even  though 
the  nerves  are  intact ;  conversely  direct  electrical  stim- 
ulation of  the  pituitary  induces  glycosuria.  These 
observations  make  it  appear  probable  that  piqure 
glycosuria  is  brought  about  by  discharging  into  the 

6  Bang:  Hofmeister's  Beitrag.,  1907,  g,  p.  408;  io,  p.  1. 
•Macleod:  Amer.  Jour.  Physiol.,  1911,  vn,  p.  403. 
"Weed,  Cushing,  and  Jacobson:  Bull.  Johns  Hopkins  Hospital,  1913, 
xxiv,  p.  40. 


EXPERIMENTAL  GLYCOSURIA  41 

circulation  some  substance  contained  in  the  posterior 
lobe  of  the  hypophysis.  This  discharge  can  be  effected 
by  nervous  stimulation  or  mechanically.  The  meaning 
of  these  experiments  is  that  the  hypophysis  (pars  ner- 
vosa) is  essential  to  piqure  glycosuria,  and  the  mode 
of  operation  of  the  puncture  is  in  some  manner  con- 
nected with  a  discharge  of  the  internal  secretion  of 
that  gland.  Two  glands  of  internal  secretion  then, 
the  adrenals  and  the  pituitary,  are  essential  in  piqure 
glycosuria ;  the  removal  of  either  effectually  prevents 
the  glycogenolysis  which  ordinarily  follows  the  Ber- 
nard puncture.  What  inter-relation  these  glands  may 
have  to  each  other  we  are  at  present  only  able  to  con- 
jecture. Further  experiments  are  required  to  eluci- 
date this  most  interesting  and  complex  problem. 

The  effect  of  adrenal  extract  in  causing  sugar  to 
be  excreted  in  the  urine  as  noted  by  Blum  X1  has  been 
confirmed  by  many  investigators,  but  Herter  and 
Wakeman  gave  the  first  intimation  of  the  significance 
of  the  phenomenon  by  showing  that  sugar  appeared 
in  the  urine  after  painting  the  pancreas  with  adrenal 
extract,  whereas  similar  applications  to  the  other  or- 
gans were  not  invariably  followed  by  this  effect.  Be- 
fore following  this  line  of  thought  further  some  of  the 
effects  of  adrenal  extract  on  the  sugar  storehouse 
must  be  noted. 

"Blum:  Deuts.  Archiv  f.  klin.  Med.,  1901,  lxxi,  p.  146. 
4 


42  DIABETES  MELLITUS 

The  glucose  excretion  appears  to  depend  upon  the 
concentration  of  epinephrin  in  the  blood,  hence  the 
effect  of  a  single  administration  is  not  of  long  dura- 
tion. The  immediate  cause  of  the  glycosuria  is  that 
the  blood  sugar  is  increased  in  amount;  this  hyper- 
glycemia, in  turn,  being  the  result  of  the  rapid  trans- 
formation of  stored  glycogen  into  circulating  sugar. 
Epinephrin  glycosuria  causes  a  rapid  disappearance 
of  hepatic  glycogen,  but  according  to  some  investi- 
gators muscle  glycogen  is  exhausted  even  more  rap- 
idly.12 This  has  been  disputed,  however.  That  epi- 
nephrin fails  to  produce  glycosuria  when  the  glycogen 
stores  are  depleted  is  evidenced  by  those  experiments 
where  the  animal  was  first  rendered  glycogen-free  by 
fasting  and  phlorhizin.  This  procedure  would  de- 
prive the  animal  of  its  glycogen ;  and  if  now  epineph- 
rin be  administered  but  little  if  any  excess  glucose 
appears  in  the  urine.13 

These  experiments  give  the  most  probable  inter- 
pretation of  epinephrin  glycosuria  as  an  increased 
glycogenolysis.  If  this  explanation  be  correct  this 
form  of  experimental  diabetes  is  quite  similar  to  that 
of  piqure  in  so  far  as  the  source  of  the  sugar  is  con- 
cerned.   It  is  quite  possible,  however,  that  there  may 

13  Kutschmer:  Arch.  f.  exper.  Patholog.  u.  Pharm.,  1907,  57,  p.  423. 
Agadshanianz:  Biochem.  Zeitschr.,  1906,  2,  p.  148. 
"Ringer:  Jour.  Exp.  Med.,  1910,  12,  105. 


EXPERIMENTAL  GLYCOSURIA  43 

be  also  a  diminished  destruction  of  glucose.  In  any 
case  the  deprivation  of  the  body  of  a  large  part  of  the 
available  glycogen  as  a  result  of  epinephrin  glycosuria 
would  excite  an  increased  protein  metabolism  as  noted 
by  Kraus  and  also  by  Eppinger.  The  chief  points 
of  relation  between  the  piqure  diabetes  and  that  in- 
duced by  epinephrin  are  then :  ( 1 )  both  depend  on  the 
presence  of  glycogen  in  the  tissues;  (2)  piqure  is  in- 
operative after  division  of  the  splanchnic  nerves,  while 
epinephrin  is  active;  (3)  piqure  is  inoperative  after 
removal  of  the  adrenal  glands.  The  latter  fact  in 
particular,  as  will  be  seen  in  connection  with  pancre- 
atic diabetes,  leads  to  an  attractive  theory  which  would 
explain  piqure  glycosuria  as  dependent  upon  adrenal 
secretion  for  its  result.  There  are  also  some  experi- 
ments to  be  mentioned  which  are  most  interesting,  but 
the  results  cannot  at  present  be  accepted  as  facts  be- 
cause sufficient  confirmation  is  yet  lacking.  On  some 
of  these  inadequate  foundations  theories  of  human 
diabetes  have  been  based.  Some  of  the  observations 
already  mentioned  give  an  intimation  that  the  glyco- 
suria resulting  from  adrenal  extract  and  that  from 
injuries  to  the  nervous  system  are  in  some  way  closely 
related.  This  idea  would  be  in  accord  with  current 
theories  of  the  chromaffin  system.  Epinephrin  ac- 
cording to  several  investigators  produces  its  effects 


44  DIABETES  MELLITUS 

through  the  peripheral  sympathetic  nerves.14  The 
sole  difference,  then,  in  the  two  types  of  glycosuria 
would  be  that  in  the  one  case,  piqure,  the  excitation 
is  central;  while  in  the  other,  epinephrin,  the  excita- 
tion is  peripheral.  This  conception  of  epinephrin  ac- 
tion is,  however,  disputed.15  If  the  action  of  epinephrin 
be  primarily  through  the  sympathetic  system  then  any 
substance  which  temporarily  paralyzes  this  system 
would  in  consequence  prevent  adrenal  glycosuria. 
Nicotine  is  believed  to  depress  the  sympathetic  system 
and  Hirayama  16  reported  experiments  where  the  gly- 
cosuria due  to  epinephrin  was  prevented  by  nicotine. 
Likewise  Eppinger,  Falta,  and  Rudinger 17  found 
that  pilocarpine  prevents  the  glycosuria  due  to  epine- 
phrin. This  latter  observation  involves  a  second  hy- 
pothesis which  will  be  best  considered  in  relation  with 
pancreatic  diabetes.  It  is  quite  conceivable  that  the 
effects  of  nicotine  and  pilocarpine,  both  of  which  are 
vaso-dilators,  are  explicable  in  the  light  of  Neubauer' s 
careful  work.  It  was  shown  by  Neubauer  18  that  other 
agents  besides  epinephrin  which  act  on  the  peripheral 

"Dixon:  Jour.  Physiol.,  1903,  xxx,  p.  97.  Macfee:  Jour.  Physiol., 
1903,  xxx,  p.  264. 

"Schafer:  Brit.  Med.  Jour.,  1908,  June  6,  p.  1347. 

"Hirayama:  Zeit.  f.  exp.  Path.  u.  Therap.,  1911,  8,  p.  649. 

17  Eppinger,  Falta,  and  Rudinger:  Zeit.  f.  klin.  Med.,  1908,  66,  1909, 
67,  380. 

"  Neubauer:  Biochem.  Zeitschr.,  1912,  xliii,  p.  335.  It  was  noted  by 
Cushing  that  chloretone  prevents  both  piqure  and  adrenalin  diabetes. 


EXPERIMENTAL  GLYCOSURIA  45 

blood-vessels  and  raise  blood-pressure  also  induce  gly- 
cosuria; barium  chloride  is  an  example.  Here  vaso- 
constriction and  glycosuria  are  concomitant.  On  the 
other  hand  drugs  of  the  narcotic  group,  for  example, 
opium,  chloral,  and  alcohol,  which  act  on  the  central 
nervous  system,  often  check  or  diminish  the  intensity 
of  glycosuria  following  piqure.  These  drugs  produce 
this  effect  by  an  action  opposite  to  that  of  epineph- 
rin-vaso-motor  paralysis  and  lowered  blood-pressure. 
Neubauer  has  also  noted  that  peripheral  vasocon- 
striction is  accompanied  by  hyperemia  of  the  liver. 
Now  any  procedure  which  induces  hyperemia  along 
with  stasis  in  the  liver  is  apt  to  give  rise  to  glucose  ex- 
cretion. These  conditions  of  asphyxia  appear  to  favor 
the  transformation  of  hepatic  glycogen  into  glucose. 

EXPERIMENTAL    PANCREATIC   DIABETES 

The  work  of  von  Mering  and  Minkowski 19  is  now 
so  well  known  that  a  review  of  it  seems  hardly  neces- 
sary. The  fact  established  and  confirmed  by  many 
different  investigators  is  that  total  ablation  of  the 
pancreas  in  animals  causes  a  severe  diabetes  which  is 
fatal.  For  a  considerable  period  the  glycosuria  fol- 
lowing this  operation  was  by  some,  notably  Pfliiger, 

19  Von  Mering  and  Minkowski:  Zentralblatt  f.  klin.  Med.,  1889,  io, 
p.  393;  Arch.  f.  exp.  Path.  u.  Pharm.,  1889,  26,  p.  371.  Minkowski:  Un- 
tersuchung  ii.  d.  Diabetes  mellitus  nach  exstirpation  d.  Pancreas.  Leipzig, 
1893. 


46  DIABETES  MELLITUS 

attributed  not  to  the  deprivation  of  the  pancreas,  but 
to  the  injury  of  nerves  in  the  process  of  pancreatic  re- 
moval. This  objection  was  overcome  by  Minkowski,20 
who  succeeded  in  transplanting  small  portions  of  pan- 
creas under  the  skin  of  animals  from  which  the  pan- 
creas had  been  removed.  In  these  animals  only  a 
slight  or  no  sugar  excretion  occurred;  but  if  subse- 
quently the  transplanted  portions  were  removed  the 
usual  diabetes  ensued.  Pancreatic  tissue  has  been 
transplanted  into  the  spleen  with  the  same  result.21 
Pfliiger  also  opposed  the  idea  of  glycosuria  resulting 
from  removal  of  the  pancreas  because  he  noted  that 
extirpation  of  the  duodenum  in  frogs  was  followed  by 
sugar  excretion.  Pfliiger  kept  his  frogs  chilled  fol- 
lowing the  operation,  and  this  is  prone  to  cause  glu- 
cose excretion  with  frogs.22  Von  Mering  removed 
the  duodenum  from  dogs  without  any  consequent  dia- 
betes. 

If  the  pancreatic  ducts  be  ligated  there  results  an 
atrophy  of  the  secreting  cells.  After  months  the  only 
remnant  of  the  gland  left  is  a  "thin  film  of  opalescent 
tissue"  composed  mostly  of  the  islands  of  Langer- 
hans.23    As  a  rule  no  diabetes  develops  in  consequence 

20  Minkowski:  Arch.  f.  exp.  Path.  u.  Pharm.,  1893,  31,  p.  85.    Hedon: 
Diabete  pancreatique.    Paris,  1908. 

21  Martina:  Deutsch.  med.  Wochenschr.,  1908,  34,  p.  45. 

22  Rosenberg:  Biochem.  Zeitschr.,  1909,  xvm,  p.  95. 

"Schulze:  Arch  f.  mikr.  Anat.  u.  Entwicklungs  gesch.,  1900,  lvi, 
p.  491. 


EXPERIMENTAL  GLYCOSURIA  47 

of  this  simple  atrophy  but  takes  place  at  once  if  the 
remnant  be  removed.24  Pratt  claims  that  there  is  a 
diminution  in  the  assimilation  limit  for  glucose  with 
dogs  following  ligation  of  the  ducts  and  atrophy  of  the 
pancreas.  These  experiments  are  all  founded  on  those 
of  Sandmeyer,25  who  in  addition  to  ligating  the  pan- 
creatic ducts  removed  a  part  of  the  gland  and  ob- 
served that  diabetes  developed  after  an  interval.  This 
last  was  the  only  experiment  that  appeared  to  Pfluger 
to  be  at  all  convincing  of  the  pancreas'  relation  to  gly- 
cosuria. The  fact  that  impressed  Pfluger  was  the 
gradual  development  of  the  glycosuria  contempo- 
raneously with  the  gradual  atrophy  of  the  pancreatic 
remnant.  This  is  not  what  would  be  expected  of  a 
nerve  injury  and  Pfluger  26  had  contended  that  pan- 
creatic removal  was  a  nerve  injury. 

It  is  generally  accepted  to-day  among  physio- 
logists that  total  removal  of  the  pancreas  causes  a 
fatal  diabetes.  But  how  this  is  brought  about  is  not 
decided.  In  the  first  place  there  is  a  hyperglycemia 
and  a  rapid  withdrawal  of  glycogen  from  the  body. 
To  account  for  the  conditions  von  Mering  and  Min- 

24  Pratt:  Arch.  Int.  Med.,  1911,  vn,  p.  665.  McCallum:  Bull.  Johns 
Hopkins  Hospital,  1909,  xx,  p.  265. 

26  Sandmeyer:  Zeitschr.  f.  Biol.,  1895,  xxxi,  p.  12. 

M  See  many  papers  by  Pfluger  in  Arch  f.  d.  ges.  Physiol.,  1907-1909. 
Pfliiger's  papers  are  worthy  of  study  by  every  physician  because  they 
show  what  evidence  is  required  to  demonstrate  an  hypothesis.  He  draws 
the  line  black  and  clear  between  what  may  be  and  what  is  proved  to  be. 


48  DIABETES  MELLITUS 

kowski  offered  two  possible  explanations:  (1)  The 
pancreas  normally  destroys  some  toxic  or  ferment  sub- 
stance; when  the  pancreas  is  removed  this  substance 
accumulates  and  causes  sugar  to  be  excreted.  (2) 
Destruction  of  sugar  in  the  body  normally  depends  in 
some  way  on  the  pancreas;  when  the  pancreas  is  re- 
moved sugar  is  no  longer  burned.  The  second  hypoth- 
esis is  the  idea  of  an  internal  secretion  although  von 
Mering  and  Minkowski  did  not  use  that  term  in  their 
early  papers.  Virchow  27  had  conjectured  years  be- 
fore that  the  pancreas  had  an  internal  secretion  but  he 
did  not  connect  it  with  sugar  metabolism.  Among 
clinicians  this  conception  had  been  held  by  Bouchardet, 
Frerichs,  and  Lancereaux  in  relation  to  sugar  metab- 
olism. Many  experiments  have  been  devised  to 
demonstrate  the  presence  in  the  blood  of  an  internal 
secretion  of  the  pancreas;  among  the  earliest  was 
Lepine's.2S  He  attempted  to  show  that  the  glycolytic 
power  of  the  blood  of  an  animal  rapidly  diminished 
after  the  pancreas  is  removed,  but  these  claims  were 
quickly  undermined.  The  variations  observed  by 
Lepine  were  due  to  post-mortem  changes  in  the  blood.29 
Many  other  experiments  with  blood  have  promised 
much  but  have  been  unable  to  withstand  searching 

27  "  und  das  auch  diese  Druse  nicht  bloss  nach  aussen  sondern  auch 
nach  innen  in  das  Blut  secernire."    Virchow:  Arch.,  1854,  7,  p.  580. 

28  Arch.  med.  Exper.,  1891,  p.  222. 

28  Kraus:  Zeitschr.  f.  klin.  Med.,  1892,  xxi,  p.  315. 


EXPERIMENTAL  GLYCOSURIA  49 

criticism.  Among  the  most  ingenious  are  those  em- 
pancreas  normally  destroys  some  toxic  or  ferment  sub- 
was  devised  by  Sauerbruck  and  consists  in  uniting  two 
animals  so  that  there  is  a  communication  between  the 
peritoneal  cavities  and  an  exchange  of  blood  and 
lymph  between  the  animals.  It  has  been  found  that 
the  parabiosis  of  a  normal  dog  with  one  from  which 
the  pancreas  has  been  removed  results  in  either  pre- 
venting or  ameliorating  the  severity  of  the  diabetes  to 
a  marked  extent.  The  explanation  offered  is  that  the 
normal  dog  furnishes  through  the  blood  some  sub- 
stance which  enables  the  depancreatized  dog  to  utilize 
sugar.30  This  is  possible  but  the  experiments  are  not 
conclusive.  As  the  vascular  systems  of  the  two  dogs 
were  in  communication  this  alone  would  diminish  the 
degree  of  hyperglycemia  of  the  depancreatized  animal 
and  that  the  sugar  content  of  the  normal  dog's  blood 
was  raised  is  evidenced  by  occasional  glycosuria.  The 
normal  dog  may  have  stored  up  sugar  as  glycogen  also. 
These  and  other  objections  that  can  be  raised  against 
the  results  of  Forschbach's  experiments  make  it  doubt- 
ful if  our  knowledge  has  been  increased  by  them. 

Cohnheim's  interpretation  of  his  experiments,31 
had  they  been  confirmed,  would  have  added  consider- 

30  Forschbach :  Deutsch.  med.  Wochenschr.,  1908,  39,  p.  910;  Arch.  f. 
exp.  Path.  u.  Pharm.,  1909,  60,  p.  121. 

^Cohnheim:  Zeit.  f.  physiol.  Chem.,  1903,  39,  p.  336;  1904,  42,  401; 
1905,  43,  p.  547;  1906,  47,  p.  253. 


50  DIABETES  MELLITUS 

able  evidence  to  support  the  hypothesis  of  an  internal 
pancreatic  secretion  relative  to  carbohydrate  metab- 
olism. Cohnheim  noted  that  when  an  extract  of  pan- 
creas and  muscle  together  are  allowed  to  act  upon 
glucose,  part  of  the  glucose  disappears  whereas  either 
extract  alone  does  not  effect  this  destruction.  The 
simple  fact  of  the  disappearance  of  sugar  from  these 
tissue  extracts  is  pretty  well  attested  by  a  number  of 
chemists.32  Interpretations  have  differed.  There  is 
now  evidence  that  the  glucose  is  not  destroyed  but  is 
transformed,  polymerized  into  higher  carbohydrates.33 
It  might  be  contended  from  these  experiments  that 
pancreatic  activity  is  requisite  for  the  storage  of  sur- 
plus sugar  as  glycogen,  but  this  hypothesis  would  ex- 
plain only  post-prandial  sugar  excretion.  There 
would  be  simply  a  diminution  in  tolerance  for  carbo- 
hydrate food.  The  hyperglycemia  of  depancreatized 
animals  during  fasting  is  unexplained.  While  the 
gross  effect  on  carbohydrate  metabolism  of  removal 
of  the  pancreas  is  hardly  questioned,  an  internal 
secretion  which  influences  the  destruction  of  glucose 
in  the  body  has  not  been  demonstrated  by  the  experi- 
ments above  mentioned.  Hedon  contended  that  the 
internal  secretion  of  the  pancreas  must  remain  a  pure 
hypothesis  until  it  is  possible  to  isolate  from  that 

83  Hall:  Amer.  Jour.  Physiol.,  1907,  18,  p.  283. 
"Levene  and  Meyer:  Jour.  Biol.  Chem.,  1911,  g,  p.  97. 


EXPERIMENTAL  GLYCOSURIA  51 

gland  a  substance  which,  administered  to  depancreat- 
ized  dogs,  will  prevent  the  glycosuria.  An  extract 
of  pancreas  was  made  by  Zulzer,  who  claimed  that 
its  administration  prevented  adrenal  glycosuria. 
Zulzer  34  also  believed  that  he  observed  favorable  re- 
sults in  human  diabetes  following  the  use  of  his  ex- 
tract, but  Forschbach  35  found  the  symptoms  following 
the  administration  of  such  a  nature  that  he  considered 
the  extract  a  dangerous  medicament.  It  seems  quite 
probable  that  Zulzer' s  results  are  due  to  the  toxic 
action  of  the  extract,36  although  there  is  the  observa- 
tion of  Fugoni 3T  that  pancreatic  extract  destroys 
adrenal  extract  in  vitro,  which  if  true  would  give  some 
basis  for  Zulzer 's  results.  The  latter  investigator  as- 
serts on  the  basis  of  his  experiments  that  glycosuria 
does  not  follow  removal  of  the  pancreas  if  the  adrenals 
are  also  extirpated,  and  even  when  they  are  left  intact 
but  the  veins  ligated  the  glycosuria  resulting  from 
pancreatic  removal  is  slight.38  In  view  of  the  notable 
difficulty  of  complete  pancreatectomy  these  experi- 

"Ziiker:  Berlin,  klin.  Wochenschr.,  1907,  44,  p.  474;  Zeitschr.  f. 
exper.  Path.  u.  Therap.,  1908,  v,  p.  307. 

33  Forschbach :  Deutsch.  med.  Wochenschr.,  1909,  35,  p.  2053. 

M  Lymph  and  peptone  both  prevent  adrenal  glycosuria.  Biedl.  and 
Offer:  Wien.  klin.  Wochenschr.,  1907,  20,  p.  1530.  Glaessner  and  Pick: 
Zeit.  f.  exp.  Path.  u.  Therap.,  1909,  6,  p.  313. 

"Fugoni:  Arch.  ital.  de  Biol.,  1908,  50,  p.  209. 

88  Berlin,  klin.  Wochenschr.,  1901,  p.  1209;  Deutsch.  med.  Wochenschr., 
1908,  32,   p.   1309. 


52  DIABETES  MELLITUS 

merits  require  confirmation.  If  true  they  bring  pan- 
creatic diabetes  within  the  range  of  the  chromaffin 
system.  Ziilzer  holds  that  pancreas  diabetes  is  not 
primarily  pancreatic  but  primarily  adrenal  in  origin. 

The  conclusions  of  Ziilzer  are  negated  quite  de- 
cisively by  the  experiments  of  Allen39  whose  work 
overthrows  the  frail  structure  of  the  polyglandular 
doctrine  of  diabetes. 

There  is  some  evidence  which  suggests  that  the 
inner  secretion  of  the  pancreas  acts  conjointly  with 
the  liver.  In  frogs  Marceus  found  that  no  sugar  is 
excreted  after  pancreatic  removal  if  the  liver  is  ex- 
cised also.  With  higher  animals  removal  of  the  liver 
is  not  compatible  with  life  but  the  desired  conditions 
have  been  approached  by  ligation  of  vessels  and  under 
these  conditions  but  very  scanty  sugar  excretion  re- 
sults. The  difficulties  surrounding  the  experiment 
preclude  decisive  results  chiefly  because  of  the  short 
space  of  time  that  such  experimental  animals  live.  In 
this  connection  the  work  of  Hedon  is  of  interest. 
Pancreatic  tissue  transplanted  into  the  carotid- jugular 
circulation  does  not  prevent,  according  to  this  in- 
vestigator, glycosuria  in  depancreatized  dogs,  but  the 
sugar  excretion  sinks  markedly  when  the  pancreas 
tissue    is    implanted    into    the    portal    circulation. 

89  Allen,  loc.  cit.,  p.  847.     See  also  Lusk:  Arch.  Int.  Med.,  1914,  xiii, 
673. 


EXPERIMENTAL  GLYCOSURIA  53 

Hedon 40  also  found  that  serum  from  the  blood  of  the 
pancreatic  vein  of  a  normal  dog  injected  into  the  por- 
tal circulation  of  a  depancreatized  dog  was  followed 
by  a  dwindling  of  the  glucose  excretion  almost  to  nil. 

These  various  observations  taken  at  their  face 
value  suggest  that  the  internal  secretion  of  the  pan- 
creas is  of  the  nature  of  a  hormone.  The  net  result 
of  all  the  experiments  attempting  to  disclose  an  in- 
ternal pancreatic  secretion  is :  that  while  it  has  not  been 
satisfactorily  demonstrated  it  seems  possible  that  such 
a  secretion  is  elaborated  and  discharged  into  the  blood. 
From  what  we  know  of  internal  secretions  in  general 
that  of  the  pancreas  probably  does  not  produce  its 
effect  directly  but  acts  rather  with  other  enzymes  in 
effecting  the  metabolism  of  glucose. 

Several  attempts  have  been  made  experimentally 
to  disclose  a  relation  between  the  pancreas  and  other 
organs  of  internal  secretion.  The  ideas  of  Zulzer 
have  already  been  referred  to.  Falta  and  his  collabo- 
rators think  that  the  thyroid  is  linked  with  pancreatic 
activity  in  the  metabolism  of  sugar.  Falta 41  claimed 
that  adrenalin  does  not  lead  to  sugar  excretion  with 
thyroidectomized  dogs  but  this  claim  was  refuted  by 
careful  experiments  of  Underbill 42  and  by  Grey. 

40  Hedon:  Compt.  rend.  Soc.  Biol.,  1911,  71,  p.  124. 
^Zeitschr.  f.  klin.  Med.,  1908,  66,  p.  1;  1909,  68,  p.  205. 

42  Amer.  Jour,  of  Physiol.,  1910,  27,  p.  331. 

43  Jour,  of  Exp.  Med.,  1909,  xi,  p.  659. 


43 


54  DIABETES  MELLITUS 

This  breaks  an  essential  link  in  Falta's  deductions 
which  join  the  thyroid  and  adrenal  in  the  causation  of 
diabetes. 

Falta's  hypothesis  and  that  of  Ziilzer  are  alike  in 
so  far  as  the  mutual  relations  of  pancreas  and  adrenal 
are  concerned.  The  conception  offered  is  that  the 
secretion  of  the  adrenal  glands  promotes  the  transfor- 
mation of  liver  glycogen  into  glucose ;  the  pancreatic 
function  inhibits  this  transformation;  pancreas  and 
adrenal  are  antagonistic  in  their  relation  to  glycogen 
transformation.  If  the  pancreas  be  removed  from  an 
animal  the  inhibiting  influence  to  glycogenolysis  is 
lost  and  adrenal  glycosuria  results.  It  is  a  proper  ob- 
jection to  interpose  here  that  in  no  diabetic  state,  even 
when  associated  with  increased  blood-pressure,  has 
there  been  demonstrated  increased  epinephrin  in  the 
blood.  Again  it  is  claimed  in  support  of  this  theory 
that  injections  of  extracts  of  pancreas  prevent  adrena- 
lin glycosuria,  but  it  has  also  been  shown  that  many 
other  tissue  extracts  prevent  adrenalin  glycosuria,  so 
nothing  specific  for  the  pancreas  can  be  claimed  by 
that  fact.  It  is  difficult  on  examination  to  find  ade- 
quate foundation  for  the  basal  conception  of  this  doc- 
trine. As  an  elaboration  of  this  theory  it  is  believed 
by  the  von  Noorden  school  that  the  pancreas  is  under 
the  control  of  the  thyroid,  which  inhibits  its  action,  and 
the  thyroid  in  turn  is  influenced  by  the  pituitary.    The 


EXPERIMENTAL  GLYCOSURIA  55 

whole  elaborate  mechanism  is  dominated  by  the  ner- 
vous system  through  the  vagus  and  sympathetic,  which 
either  promotes  or  inhibits  the  several  glandular  activi- 
ties.44 In  criticism  it  may  be  acknowledged  that  iso- 
lated facts  suggest  on  superficial  consideration  the 
relation  of  various  glands  with  glycosuria,  e.g.,  acro- 
megaly; but  the  establishment  of  so  complex  a  doc- 
trine as  the  one  outlined  is  most  difficult  since  it 
demands  variations  in  experimental  technic  and  the 
combined  ablation  of  the  two  organs  without  which  in 
some  instances  life  can  be  supported  only  for  the 
briefest  periods. 

phlorhizin  45 

The  glycosuria  due  to  phlorhizin  has  been  very 
thoroughly  studied.  From  the  time  of  its  discovery 
by  von  Mering  down  to  the  present  it  has  continued 
to  engage  the  interest  of  physiologists,  not  because 
phlorhizin  diabetes  is  in  any  way  related  to  human 
diabetes  but  rather  because  by  this  means  many  prob- 
lems in  carbohydrate  metabolism  may  be  submitted  to 
experimental  test.  In  striking  contrast  to  other  forms 
of  experimental  glycosuria  the  blood  in  phlorhizinized 

44  For  an  exposition  of  these  theories  see  von  Noorden :  Med.  Klinik., 
1911.  vii,  No.  1,  p.  1,  and  a  criticism  of  them.  Minkowski:  ibid.,  1911,  vn, 
No.  27,  p.  1031. 

45  For  the  complete  literature  see  Lusk:  Phlorhizin  Diabetes,  Ergeb- 
nisse  d.  Physiolog.,  1912. 


56  DIABETES  MELLITUS 

dogs  contains  less  sugar  than  normal;  there  is  a  hy- 
poglycemia. It  is  generally  assumed  at  present  that 
the  glucose  excretion  induced  by  phlorhizin  is  effected 
by  action  upon  the  kidney.  This  theory  rests  upon 
the  experiment  of  Zuntz  who  injected  in  the  renal 
artery  of  one  kidney  a  solution  of  phlorhizin  and  ob- 
served that  sugar  was  excreted  from  this  kidney  an 
appreciable  time  before  it  appeared  in  the  urine  from 
the  other  kidney.  Minkowski  believed  that  phlorhizin 
is  broken  up  in  the  body  into  glucose  and  phloretin, 
the  latter  acts  as  a  carrier  of  blood  sugar  to  the  kidney 
where  the  combination  is  broken  up  and  the  sugar  ex- 
creted, while  the  phloretin  is  retained  and  combines 
with  more  blood  sugar.  There  is  a  constant  but  slow 
excretion  of  this  phloretin  also,  hence  the  effect  of  the 
initial  dose  slowly  wears  off.  It  seems  doubtful,  how- 
ever, that  the  sole  effect  of  phlorhizin  is  through  the 
medium  of  the  kidneys,  since  Grube  noted 46  that  in 
perfusing  the  livers  of  turtles  more  sugar  was  taken  up 
by  the  perfusion  fluid  when  it  contained  phlorhizin  in 
addition  to  the  other  ingredients.  This  experiment 
would  indicate  that  phlorhizin  increases  the  breaking 
down  of  liver-glycogen  into  sugar,  which  is  so  rapidly 
excreted  through  the  kidneys  that  it  is  not  burned. 

The  results  of  the  study  of  phlorhizin  glycosuria 
have  been  already  mentioned  in  connection  with  sugar 

46   Pflugers  Arch.,  1909,  128,  p.  118. 


EXPERIMENTAL  GLYCOSURIA  57 

metabolism.  They  require  now  only  passing  mention. 
It  was  noted  by  Lusk  that  in  the  first  two  or  three 
days  if  dogs  are  kept  under  the  influence  of  phlorhizin 
the  sugar  excretion  is  large  but  later  this  falls  some- 
what. This  initial  sugar  excretion  Lusk  attributes  to 
the  removal  of  stored  glycogen  from  the  tissues.  After 
the  glycogen  is  removed  there  is  a  fairly  constant  re- 
lation of  dextrose  excretion  to  nitrogen  excretion 
which  is  usually  about  3.6  to  1.  Lusk  believes  that  in 
the  thoroughly  phlorhizinized  dog  no  glucose  is  util- 
ized, hence  the  dextrose-nitrogen  ratio  represents  the 
maximum  sugar  derivable  from  protein.  Since  one 
gramme  of  nitrogen  represents  6.25  grammes  of  pro- 
tein the  Lusk  ratio  would  indicate  that  each  100 
grammes  of  protein  may  yield  57  grammes  of  glucose, 
an  amount  considerably  in  excess  of  that  indicated  by 
the  ratio  in  depancreatized  dogs.  The  question  arises 
in  relation  to  phlorhizin  diabetes :  Is  all  the  sugar  from 
protein  excreted  in  the  urine  or  is  a  constant  fraction 
catabolized?  On  the  basis  of  their  experiments  Falta 
claimed  that  a  ratio  still  higher  than  3.6  could  be  se- 
cured by  administering  epinephrin  to  phlorhizinized 
dogs.  The  deductions  that  were  drawn  from  these  ex- 
periments are  of  no  value  since  Ringer  has  conclusively 
shown  that  epinephrin  is  devoid  of  effect  upon  the 
ratio  if  the  experimental  animals  have  been  completely 

freed  of  tissue  glycogen.    Moreover,  in  recent  experi- 
5 


58  DIABETES  MELLITUS 

ments  Lusk  has  found  the  respiratory  quotient  so  low 
in  completely  phlorhizinized  dogs  that  the  combustion 
of  carbohydrates  seems  excluded. 

Phlorhizin  glycosuria  has  been  most  productive  of 
interesting  results  by  furnishing  a  means  of  insight 
into  the  transformation  of  protein  into  sugar.  Lusk 
has  in  this  way  disclosed  that  some  of  the  amino-acids 
of  which  protein  is  composed  are  wholly  transformed 
into  sugar,  while  others  are  without  effect  on  the  sugar 
excretion.  These  amino-acids  have  already  been  re- 
ferred to  in  considering  the  derivation  of  sugar  from 
protein. 


IV 

ACIDOSIS 

For  the  perfect  performance  of  the  chemical  func- 
tions in  the  body  it  is  necessary  that  the  tissue  fluids 
preserve  a  certain  reaction.  Normally  there  is  a  very 
small  excess  of  potential  alkaline  over  acid  radicles. 
The  blood  is  practically  neutral.  In  the  physiological 
processes  there  are  constantly  being  formed  as  prod- 
ucts of  catabolism  various  acids  which  are  either  de- 
stroyed by  further  oxidation  or  are  neutralized  and 
excreted  as  salts  and  even  when  considerable  quantities 
of  mineral  acids  are  ingested  there  is  no  appreciable 
change  in  the  reaction  of  the  blood  and  tissues.  The 
body  has  in  health  sufficient  reserves  of  alkalies  to 
meet  these  ordinary  demands.  In  morbid  states,  how- 
ever, the  accumulation  of  acid  radicles  may  be  very 
large  and  tax  the  defense  mechanism  of  the  organism 
to  the  utmost.  The  earliest  manifestation  of  this  ex- 
cessive acid  production  is  to  be  noted  in  the  increased 
acidity  of  the  urine.  With  many  febrile  states,  for 
example,  rheumatic  fever,  the  urine  is  strongly  acid 
and  often  persists  so  notwithstanding  the  ingestion  of 
considerable  amounts  of  alkalies.  Strictly  speaking 
the  conditions  where  there  is  an  excessive  production 
of  acids  can  be  referred  to  as  an  acidosis.     Under 

59 


60  DIABETES  MELLITUS 

these  circumstances  the  production  of  acids  does  not 
necessarily  lead  to  a  predominance  of  acid  radicles  in 
the  tissue  fluids,  since,  besides  the  available  sodium, 
potassium,  and  calcium,  the  organism  furnishes  am- 
monia on  demand  to  combine  with  the  acids  and  form 
neutral  compounds.  It  is  not  demonstrated  that  the 
acid  production  accompanying  fevers  and  allied  con- 
ditions is  so  great  as  to  give  rise  to  clinical  symptoms 
and  the  amounts  of  acids  formed  are  relatively  trivial 
compared  with  the  excretion  in  diabetes  mellitus.1 

Since  the  acid  in  excess  of  amounts  that  are  neu- 
tralized by  the  fixed  bases  combines  with  ammonia 
and  is  excreted  as  an  ammonia  salt  it  is  evident  that 
increased  ammonia  in  the  urine  is  a  rough  index  of  the 
degree  of  acidosis ;  the  second  test  of  acidosis  is  an  in- 
crease in  the  acid  radicles  (H  ions)  over  the  alkaline 
(OH  ions)  in  the  blood.  On  account  of  the  decrease 
in  alkalies,  the  blood  is  less  able  to  hold  C02.  There  is 
then  a  decrease  in  the  C02  content  of  the  blood.  These 
tests  for  a  condition  of  acidosis  have  been  found  ful- 
filled in  experimental  conditions  and  are  met  with,  in 
some  degree,  in  diseases  associated  with  acidosis. 

In  relation  to  diabetes  the  term  acidosis  was  orig- 
inally used  by  Naunyn  to  explain  phenomena  which 

1  For  a  discussion  of  these  mild  types  of  acidosis  accompanying  va- 
rious diseases  see  Henderson:  Amer.  Jour.  Physiol.,  1908,  ai,  p-  427;  Arch. 
Inter.  Med.,  1913,  12,  pp.  146,  153. 


ACIDOSIS  61 

were  believed  to  be  the  result  of  accumulation  of  acids 
in  the  organism.  Stadelman,  a  student  of  Naunyn, 
separated  considerable  quantities  of  /3-oxybutyric 
acid  from  the  urine  of  severe  cases  of  diabetes  2  and 
recognized  a  similarity  between  the  picture  of  diabetic 
coma  and  the  experimental  acid  poisoning  produced 
in  animals  by  Walter.  When  0.7  to  0.8  gramme  of 
hydrochloric  acid  per  kilo  body  weight  is  injected  into 
the  stomach  of  a  rabbit  there  develops  a  loss  of  mus- 
cular power,  rapid  pulse,  and  a  type  of  dyspnoea  char- 
acterized by  deep  breathing  and  coma  terminating  in 
death.  There  is  also  observable  in  this  condition  a 
diminished  alkalinity  of  the  blood  and  a  decrease  in  its 
content  of  C02.  The  C02  that  could  be  extracted 
from  the  blood  fell  from  32  to  3  volumes  per  100  vol- 
umes of  blood.  These  experiments  are  the  foundation 
of  the  Naunyn- Stadelman  conception  of  diabetic 
coma  as  an  acidosis.  The  amounts  of  acids  separated 
from  the  urine  by  Stadelman  were,  however,  insuffi- 
cient to  explain  coma,  and  the  theory  rested  upon  in- 
secure basis  until  Magnus-Levy3  succeeded  in  re- 
covering from  the  tissues  of  cases  dead  of  diabetic 
coma  amounts  of  acid  which  estimated  in  relation  to 
body  weight  were  greater  than  Walter  used  in  his 

2  Stadelman  at  first  believed  this  acid  to  be  d-crotonic  acid;  it  was 
identified  as  ^-oxybutyric  acid  by  Kiilz  and  by  Minkowski. 

3 Magnus-Levy:  Arch.  f.  exp.  Path.  u.  Pharm.,  1899,  42,  p.  149;  1901, 

45,  P-  389- 


62  DIABETES  MELLITUS 

experiments.  Whether  there  is  any  other  condition 
analogous  to  diabetic  acidosis  in  that  the  accumulation 
of  some  acid  in  the  body  is  responsible  for  clinical 
symptoms  is  at  present  doubtful ;  there  is  none  where 
oxybutyric  is  the  agent,  none  with  such  an  enormous 
acid  formation  and  excretion  as  in  the  diabetic  state. 

Ketonuria,  that  is,  the  excretion  of  /^-oxybutyric 
acid,  diacetic  acid,  and  acetone  in  the  urine,  is  not 
peculiar  to  diabetic  acidosis.  There  is  normally  in  the 
daily  urine  50  to  60  milligrammes  of  acetone  which  is 
eliminated  from  the  kidneys  as  diacetic  acid,  the  trans- 
formation of  diacetic  acid  into  acetone  taking  place 
spontaneously.  The  expired  air  also  contains  a  small 
amount  of  acetone  which  leaves  the  blood  as  diacetic 
acid.  In  measuring  small  amounts  of  the  ketone 
bodies  there  is  considerable  technical  error  and  the  re- 
sults for  normal  persons  are  variously  estimated,  but 
probably  do  not  exceed  10  centigrammes  per  day. 

The  most  important  influence  in  increasing  the 
ketone  excretion  is  restriction  of  carbohydrate  of  the 
food.  It  has  been  repeatedly  noted  that  in  those  condi- 
tions where  the  ingest  of  food  or  of  starch  is  markedly 
diminished  there  results  a  ferric  chloride  reaction  in 
the  urine  (Gerhardt's  test).  This  is  the  explanation 
in  great  part  of  the  acetonuria  of  fevers,  of  severe 
gastro-intestinal  disease,  and  of  cachexia.  And  from 
this  the  question  at  once  arises  as  to  what  degree  of 


ACIDOSIS  63 

acidosis  can  be  induced  in  normal  persons  by  dietary- 
restrictions.  Hirschf  eld,  one  of  the  first  in  the  field  of 
investigation,  estimated  only  the  acetone  of  which  he 
recovered  .44  gramme  in  the  fifteenth  day  of  a  fat- 
protein  diet.  Magnus-Levy  determined  the  total 
ketone  bodies  in  his  own  urine  while  restricting  the 
diet  to  meat  and  fat  with  the  following  results : 

Total 
ketone 
Oxy-        as  oxy- 
butyria    butyric 
Day  Acetone       acid  acid 

1  0.07  0.40  0.52 

2  0.24  0.94  1.37 

3  0.45  2.10  2.9 

4  0.75  3.4  4.75 

5  0.90  4.4  6.02 

In  this  experiment  there  was  a  daily  dosage  of  20 
grammes  of  bicarbonate  of  soda,  which  has  been  shown 
to  facilitate  elimination  of  the  acids  formed.  Benedict 
and  Joslin  4  secured  the  excretion  of  8.0  grammes  of 
^-oxybutyric  acid  by  the  use  of  a  carbohydrate-free 
diet  with  a  normal  man.  While  the  formation  and  ex- 
cretion of  these  amounts  of  ketone  substances  is  sug- 
gestive it  is  comparable  only  to  the  milder  cases  of 
acidosis  in  disease.  But  Landergren  and  more  re- 
cently Forssner  5  have  secured  much  higher  values. 
The  latter  working  with  himself  as  the  experimental 
subject  attained  an  elimination  of  42  grammes  of 

4 Metabolism  in  Severe  Diabetes:  Carnegie  Institute,  No.  170,  p.  127. 
8Skand:  Arch.  f.  Physiol.,  1909,  22,  p.  349;  23,  p.  305. 


64  DIABETES  MELLITUS 

ketone  bodies  in  one  day,  an  amount  comparable  with 
many  cases  of  very  severe  acidosis  in  diabetes.  One 
other  fact  brought  out  in  Forssner's  work  deserves 
special  emphasis  and  that  is  that  the  ketonuria  may 
persist  even  after  the  normal  subject  has  ingested  con- 
siderable carbohydrate;  in  one  instance  when  40 
grammes  of  carbohydrate  were  ingested  there  was  an 
elimination  of  32  grammes  of  ketone  bodies.  It  was 
also  remarked  that  different  individuals  responded 
variously  in  their  susceptibility  to  acidosis  under  diet 
restriction — a  fact  analogous  to  disease  conditions. 
These  experiments  of  Landergren  and  Forssner  go 
very  far  in  establishing  the  fact  that  acidosis  is  purely 
the  effect  of  carbohydrate  restriction.  When  it  is  re- 
called that  the  normal  non-diabetic  organism  is  never 
without  some  carbohydrate  to  burn — in  the  experi- 
ment mentioned  40  grammes 6 — the  force  of  the  argu- 
ment is  increased.  It  seems  possible  that  if  phlorhizin 
were  used  to  prevent  the  combustion  of  sugar  derived 
from  protein  there  would  result  in  a  non-diabetic 
man  an  acidosis  as  severe  as  ever  prevails  in  diabetic 
coma.7    If  then  these  experiments  are  trustworthy  in 

*  Estimated  from  urinary  nitrogen. 

T  This  experiment  has  been  recently  made  by  my  colleague,  S.  R. 
Benedict.  A  D  :  N  ratio  of  3.6  was  secured.  The  NH3  -  N  amounted  to 
over  4  grammes;  ^-oxybutyric  acid,  32  gm.;  diacetic  acid,  5  gm,  per  day. 
In  the  experimental  period  of  about  two  weeks  over  300  gm.  of  (J-oxy- 
butyric  acid  was  eliminated.  The  acidosis  ceased  promptly  on  discontinu- 
ing phlorhizin  and  ingesting  sugar.  Proc.  Soc.  Exp.  Biol,  and  Med.,  1914, 
xi,  134. 


ACIDOSIS  65 

establishing  as  a  fact  that  severe  ketonuria  is  a  conse- 
quence only  of  carbohydrate  deprivation  this  fact 
would  be  strong  evidence  in  support  of  the  theory  that 
oxybutyric  and  diacetic  acids  are  normal  links  in  the 
disintegration  of  higher  fatty  acids. 

The  theory  that  acidosis  is  a  condition  sui  generis 
and  is  in  some  way  peculiar  to  diabetes  is  worthy  of 
examination.  Von  Noorden  8  had  taken  this  position 
for  the  following  reasons :  ( 1 )  Some  diabetics  can  ab- 
sorb and  oxidize  70  to  100  grammes  of  carbohydrate 
daily  and  still  excrete  3  to  5  grammes  of  acetone.  (2) 
Many  diabetics  develop  ketonuria  on  changing  from  a 
mixed  diet  to  one  containing  no  carbohydrate,  and  the 
ketonuria  persists  when  the  mixed  diet  is  again  re- 
sumed. ( 3 )  In  other  cases  the  ketonuria  usually  result- 
ing from  strict  diet  is  only  temporary  or  absent.  This 
can  only  be  explained  by  supposing  that  the  removal 
of  all  carbohydrate  improves  the  general  condition  and 
alleviates  the  pathological  state  which  produces  keto- 
nuria. Von  Noorden  cites  a  case  of  Satta's  where  the 
acetone  bodies  average  19  grammes  on  the  first  two 
days  of  strict  diet;  then  gradually  fell  to  1.5  grammes 
on  the  eleventh  to  the  thirteenth  days,  and  four  days 
later  were  down  to  0.8  gramme.  The  sugar  excretion 
on  the  first  two  strict  diet  days  averaged  141  grammes, 
and  fell  to  114  grammes  on  the  eleventh  to  thirteenth 

8  Metabolism  and  Practical  Medicine.    Chicago,  1907,  vol.  3,  p.  593. 


66  DIABETES  MELLITUS 

days  (that  is,  the  patient  in  the  latter  period  was  burn- 
ing 27  grammes  of  sugar  more  than  at  the  commence- 
ment of  the  diet).  (4)  Patients  of  apparently  the 
same  physical  condition  and  with  the  same  severity  of 
disorder  may  show  wide  variations  in  the  degree  of 
ketonuria.  (5)  Individual  cases  on  the  same  diet 
exhibit  variations  in  the  amounts  of  ketone  bodies 
excreted. 

It  is  von  Noorden's  conception  that  under  certain 
conditions  the  body  can  manufacture  sugar  from  fat, 
and  he  conceives  that  the  ketone  bodies  are  in  some 
way  connected  with  this  transformation.  As  we  have 
already  seen  the  origin  of  sugar  from  fat  is  absolutely 
undemonstrated. 

When  we  examine  von  Noor den's  reasons  for  con- 
sidering diabetic  acidosis  as  a  departure  from  normal 
in  relations  "not  merely  quantitative  but  qualitative 
and  fundamental,"  we  must  admit  at  once  that  not  in 
all  respects  at  present  are  the  normal  relations  entirely 
clear.  Individuals  differ,  as  Forssner  determined,  in 
the  amount  of  carbohydrate  requisite  by  combustion  to 
inhibit  ketonuria.  It  was  noted  above  that  some  nor- 
mal persons  still  excreted  ketone  bodies  in  large 
amounts  when  ingesting  40  grammes  of  carbohydrate. 
So  that  the  variability  of  the  disease  state  is  not  pecu- 
liar, as  von  Noorden  believes.  The  fact  that  some 
diabetics  first  develop  ketonuria  with  a  carbohydrate 


ACIDOSIS  67 

free  diet  or  that  a  slight  ketonuria  may  become  severe 
is  well  recognized.  There  are  severe  cases  where  the 
amount  of  sugar  utilized  is  small  and  the  margin  nar- 
row, and  when  the  ketonuria  persists  after  additions 
of  starch  to  the  diet  it  is  usually  found,  if  looked  for, 
that  this  carbohydrate  is  not  utilized.  In  other  words 
the  tolerance  has  become  slightly  less — probably  just 
enough  less  to  induce  a  persistent  acid  formation. 
With  those  individuals  where  the  ketone  excretion 
falls  during  a  period  of  carbohydrate-free  diet 
(Satta's  case)  it  is  observable  in  every  case  where  the 
data  are  sufficient  for  evidence  that  there  is  a  gradual 
and  parallel  fall  in  the  dextrose  elimination ;  i.e.*  a  rise 
in  tolerance,  which  means  more  sugar  is  burned  in  the 
body.  In  Satta's  case  cited  above,  the  difference 
amounts  to  27  grammes,  which  could  easily  effect  the 
change,  since  this  amount  was  not  all  the  sugar  burned, 
but  represented  an  addition  to  the  daily  amount  con- 
sumed at  the  commencement  of  the  diet  period.  The 
peculiarities  claimed  by  von  Noorden  for  the  acidosis 
of  diabetes,  then,  offer  no  insurmountable  obstacle  to 
the  current  theory;  since  all  the  conditions  are  either 
simulated  or  approximated  in  the  healthy  body  by 
restrictions  and  changes  in  diet.  If,  on  the  other  hand, 
it  can  be  shown  that  metabolism  during  fasting  or  with 
a  diet  devoid  of  carbohydrate  is  wholly  or  in  part 
pathological,  then  there  is  basis  for  the  conception  of 


68  DIABETES  MELLITUS 

acidosis  as  a  perversion  rather  than  a  result  of  incom- 
plete normal  process.  There  is  no  direct  evidence  on 
this  question  but  considerable  that  applies  indirectly. 
Normal  man  may  ingest  fifteen  to  twenty  grammes 
of  £-oxybutyric  acid  and  only  traces  reappear  in  the 
urine;  on  the  other  hand,  if  diacetic  be  fed  there  re- 
sults an  excretion  of  /?-oxybutyric  acid.9  When  either 
diacetic  or  /3-oxybutyric  acid  is  given  alone  to  cases 
of  severe  diabetes  both  ketones  appear  in  the  urine.10 
This  discrepancy  at  once  suggests  some  essen- 
tial change  in  the  diabetic  organism  which  will  be 
considered  subsequently.  The  subject  of  acidosis  has 
not  received  much  attention  in  experimental  diabetes, 
but  with  phlorhizinized  dogs  there  are  considerable 
quantities  of  ketone  bodies  recoverable  from  the  urine 
in  spite  of  the  fact  that  carnivorous  animals  are  not  so 
prone  to  ketonuria  as  man.  Here  again  the  phe- 
nomenon is  concomitant  with  failure  of  carbohydrate 
combustion.  The  livers  of  depancreatized  or  phlor- 
hizinized dogs  yield  more  diacetic  acid  in  perfusing 
them  than  normal  organs.  Embden  "  found  that  nor- 
mally from  12  to  27  milligrammes  of  diacetic  acid  was 
recoverable  from  a  litre  of  perfused  blood,  while  with 
diabetic  dogs  he  found  70  to  130  milligrammes  of 

"Blum:  Munch,  med.  Wochenschr.,  1910,  57,  No.  13,  p.  683. 
"Neubauer:   Verhandl.   d.   deutsch.   Kong.    f.   inn.   Med.,   1910,   27* 
pp.  666-574. 

"Embden:  Biochem.  Zeitschr.,  1908,  13,  p.  262. 


ACIDOSIS  69 

diacetic  acid.  The  extracts  of  tissues  had  not,  how- 
ever, lost  their  power  of  destroying  the  ketone  bodies. 
Now  if  it  be  assumed  that  the  ketone  bodies  result 
from  an  incomplete  oxidation  of  fatty  acids  which  nor- 
mally progresses  to  C02  and  H20  there  must  be  some 
hypothesis  as  to  the  stage  at  which  this  hindrance  to 
normal  metabolism  occurs  in  order  to  explain  the  ap- 
pearance of  two  intermediary  products :  ^-oxybutyric 
and  diacetic  acids.  It  is  quite  generally  agreed  that 
when  butyric  acid  enters  the  diabetic  organism  both 
£-oxybutyric  and  diacetic  acids  appear  in  the  urine; 
while  under  normal  physiological  conditions  all  three 
of  these  substances  undergo  complete  combustion.  It 
might  be  assumed  that  there  is  in  severe  diabetes  either 

(1)  a  defect  in  the  cleavage  of  ^-oxybutyric  acid  or 

( 2 )  a  hindrance  to  the  oxidation  of  diacetic  acid.  In 
Neubauer's  opinion  it  is  unlikely  that  processes  so 
essentially  different  should  always  be  involved  to- 
gether. He  found  on  examining  the  results  of  urine 
analyses  for  ketone  bodies  that  the  £-oxybutyric  oc- 
curred quite  constantly  as  60  to  80  per  cent,  of  the 
total  ketone  bodies.  From  this  fact  it  is  suggested  that 
there  is  a  state  of  equilibrium  in  the  tissues  between 
diacetic  and  /3-oxybutyric  acids,  and  this  equilibrium 
is  the  characteristic  state  for  a  reversible  reaction; 
according  to  current  theories 

CjHtOCOOH  <=±  C3H5OCOOH 


70  DIABETES  MELLITUS 

The  reaction  runs  normally  from  left  to  right  but  in 
grave  cases  of  diabetes  there  arises  a  difficulty  in  dia- 
cetic  destruction  in  consequence  of  which  this  sub- 
stance accumulates  and  the  reversed  reaction  occurs 
from  right  to  left.  In  order  to  test  this  hypothesis 
(that  diacetic  acid  may  go  over  into  £-oxybutyric) 
Neubauer  12  gave  large  amounts  of  diacetic  acid  (30 
grammes)  as  the  sodium  salt  to  cases  of  severe  dia- 
betes and  observed  a  rise  in  both  ketone  bodies  in 
the  urine.  The  most  probable  process  for  the  dis- 
integration of  the  fatty  acids  in  health  is  through 
£-oxybutyric  acid  to  C02  and  water  without  the 
intervening  production  of  diacetic  acid.  In  severe 
diabetes  or  carbohydrate  starvation  a  false  process  is 
initiated  in  the  oxidation  of  oxybutyric  acid  to  dia- 
cetic. This  in  turn  gives  origin  to  the  state  of  equilib- 
rium and  reversible  reaction. 


CHs 

1 

CHs 

i 

normal 

-»  C02-f-H20 

CH2    -> 

0CHOH 

i 

C/XX3 

1 

CHs 

CH2 

1 

abnormal 

-»co 

J 

COOH 

COOH 

CH2 

1 
COOH 

Dakin  13  has  shown  that  liver  tissue  may  not  only 
oxidize  £- oxybutyric  acid  to  aceto-acid,  but  also  reduce 

"Neubauer:   Verhandl.    d.   deutsch.   Kong.   f.   inn.   Med.,   1910,   27, 
pp.  566-574. 

18  Jour.  Biol.  Chem.,  1910,  8,  p.  97. 


ACIDOSIS  71 

diacetic  to  /^-oxybutyric  acid ;  the  reaction  effected  de- 
pending among  other  conditions  on  the  oxygen  supply. 


CHj.COHO.CH2.COOH  oxidase  CH3.C0.CH2.C00H 

< 

reductase 

Blum14  believes  the  normal  path  for  the  catab- 
olism  of  butyric  acid  is  by  way  of  diacetic  acid  without 
the  formation  of  /3-oxybutyric  acid  as  an  intermediate 
step.  His  experimental  results  do  not  justify  so  wide 
a  generalization.  This  explanation  would  clarify  why 
normal  persons,  in  contrast  to  severe  diabetics,  may  in- 
gest large  quantities  of  oxybutyric  acid  without  ex- 
creting diacetic  acid  in  the  urine,  but  diacetic  may  lead 
to  some  oxybutyric  excretion.  From  this  point  of 
view  £- oxybutyric  acid  is  the  only  one  of  the  ketone 
bodies  that  is  not  an  intermediary  product  in  normal 
catabolism. 

It  is  not  possible  at  present  to  give  any  satisfac- 
tory answer  to  the  question  why  the  withdrawal  of 
carbohydrates  from  the  diet  induces  an  acidosis.  It 
has  been  suggested  already  that  this  deprivation  in 
man  may  institute  an  entirely  pathological  type  of 
metabolism,  but  the  only  evidence  for  this  is  the  rela- 
tive failure  of  carnivorous  animals  (dog)  to  develop 
ketonuria  during  fasting.  Scarcely  more  satisfac- 
tory is  Geelmuy den's  assumption  of  a  synthesis  be- 

14  Miinch.  med.  Wochenschr.,  1910,  57,  p.  683. 


72  DIABETES  MELLITUS 

tween  the  ketone  bodies  and  sugar  as  necessary  for  oxi- 
dation of  the  latter.  If  sugars  are  not  burned  the 
ketones  are  not ;  which  is,  after  all,  only  a  restatement 
of  "  Das  Fat  verbrennt  im  Feuer  der  Kohlehydrat." 
This  doubtless  expresses  the  effect,  but  hardly  the 
mode  of  operation.  It  has  also  been  conjectured  that 
since  fat  in  the  diet  influences  ketonuria,  acidosis  is  in 
some  way  interlinked  with  the  mobilization  of  fat  in 
the  body  during  starvation  and  as  evidence  for  this  is 
cited  the  lipaemia  and  the  fatty  liver  of  diabetic  coma. 
The  evidence  at  present  available  indicates  that 

( 1 )  ketonuria  is  a  result  of  carbohydrate  deprivation. 
This  deprivation  is  in  effect  the  same  whether  the  car- 
bohydrate is  not  ingested  or  is  ingested  and  not 
burned.  There  is  no  essential  difference  between  the 
ketonuria  of  sugar-starvation  and  severe  diabetes. 

(2)  The  excretion  of  £-oxybutyric  acid  indicates  an  in- 
complete normal  catabolism. 

THE  MOTHER  SUBSTANCES  OF  THE  KETONE  BODIES 

The  natural  inference  made  by  the  older  investiga- 
tors that  the  ketone  bodies  are  products  of  abnormal 
carbohydrate  catabolism  is  no  longer  believed.  As 
soon  as  it  was  recognized  that  it  is  in  just  those  cases 
where  least  sugar  is  burned  that  the  acid  formation  is 
greatest,  it  then  became  apparent  that  one  must  look 
either  to  protein  or  fat  for  the  precursors  of  oxybutyric 


ACIDOSIS  73 

acid.  An  increased  excretion  of  ketone  bodies  follow- 
ing the  ingestion  of  butter  was  attributed  by  Geelmuy- 
den  to  the  lower  fatty  acids  contained  in  butter,  and 
not  until  the  studies  of  Magnus-Levy 15  disclosed  the 
enormous  formation  of  ketones  that  may  occur  was  it 
appreciated  that  all  fatty  acids  must  contribute  to 
make  up  so  large  a  sum.  Refinements  in  methods  of 
investigation  have  led  to  quite  definite  information  as 
to  the  various  organic  complexes  which  may  be  trans- 
formed into  the  ketone  bodies.  The  methods  chiefly 
employed  have  been  ( 1 )  the  administration  of  the  sub- 
stance to  be  tested  to  diabetic  patients  under  rigidly 
controlled  conditions  of  experiment  and  the  result 
noted  in  the  urinary  ketone  excretion.  (2)  The  per- 
fusion of  dogs'  liver  with  defibrinated  blood  to  which 
is  added  the  substance  for  test  and  the  total  ketone  in 
the  blood  determined  before ,and  after  perfusion.  (8) 
Administering  to  dogs  poisoned  with  phlorhizin  the 
substance  to  be  tested.  By  these  methods  a  very  large 
number  of  fatty  acids  and  amino-acids  have  been  in- 
vestigated. A  list  of  the  more  important  is  noted  in 
the  accompanying  table.16    It  is  of  interest  that  many 

15  In  one  case  there  were  excreted  in  the  urine  in  three  days  342 
grammes  of  ^-oxybutyric  acid  and  diacetic  acid,  with  nitrogen  equiv- 
alent to  271  grammes  metabolized  protein  from  which  about  120  grammes 
of  sugar  were  derived.  Joslin  has  reported  similar  studies.  Magnus- 
Levy:  loc.  cit. 

16Dakin:  Jour.  Biol.  Chem.,  1913,  14,  No.  3. 

6 


74 


DIABETES  MELLITUS 


of  the  protein  derivatives  that  are  not  ketone  precur- 
sors are  transformed  into  sugar  as  has  been  previously- 
pointed  out.  The  notable  fact  observed  in  the  table 
of  fatty  acids  is  that  those  with  an  even  number  of 
carbon  atoms  in  the  molecule  break  down  into  ketone 
bodies  while  those  with  an  odd  number  of  carbon  atoms 
do  not.  The  reason  for  this  becomes  apparent  in  con- 
sideration of  the  mode  of  oxidation  of  fatty  acids  in 
general. 


Ketogenic 


Fatty  acids 

Propionic  (CzEUCOOH) 

Butyric  (C3H7COOH) 

Valerianic  (C^COOH) .... 

Caproic  (C6HuCOOH) 

Heptylic  (CjHuCOOH) 

Octoic  (CtHi6COOH) 

Nonoic  (CsHnCOOH) 

Decoic  (C9Hi9C00H) 

Palmitic  (C15H31COOH) 

Stearic  (CnHasCOOH) 

Oleic  (CwHmCOOH) 


Perfusion 
liver 


+ 
+ 


Human 
diabetes 


+ 
+ 


+ 
+ 


Amino  acids 

Alanine 

Arginine 

Aspartic  acid 

Cystein 

Glutamic  acid 

Histidine (?) 

Leucine 

Lysine (?) 

Phenylalanine -f- 

Tyroaine -f- 


+ 

+ 

+ 


Glucogenic 

+ 

+ 


+ 

+ 

+ 

(?) 
(?) 


By  an  elaborate  series  of  experiments  Knoop  17 
has  shown  that  when  oxygen  is  united  to  the  fatty  acid 
molecule  in  the  body  this  union  occurs  with  the  /?-car- 


Knoop:  Beitr.  z.  chem.  Physiol,  u.  Path.,  1904,  6,  150. 


ACIDOSIS  75 

bon  atom.  In  the  case  of  butyric  acid  it  is  evident  that 
simple  oxidation  transforms  it  into  /2-oxybutyric  acid. 

CH,  CH, 

I  I 

0CH2  CHOH 

I  +0=| 

aCHj  CH, 

I  I 

C00H  C00H 

The  same  reaction  takes  place  with  acids  containing  a 
large  number  of  carbon  atoms;  first  an  oxidation  in 
the  beta  position,  then  in  consequence  of  further  oxida- 
tion a  split  in  the  chain  between  the  alpha  and  beta 
atoms  with  the  formation  of  an  acid  containing  two 
less  carbon  atoms  and  C02  and  H20.  In  this  manner 
the  higher  fatty  acids  are  disintegrated  to  the  lower, 
losing  two  atoms  of  carbon  by  each  oxidation.  Thus 
it  becomes  clear  why  only  fatty  acids  with  an  even 
number  of  carbon  atoms  produce  butyric  acid. 

The  position  of  the  atom  is  reckoned  from  the 
COOH  group  thus  in  caproic  acid  (C5HnCOOH), 
and  the  reaction  is  an  example  of  /^-oxidation. 

CHg  CH,  CH,  CHj 

I  I  II 

CH2  CH2  CH2+0  =  CHOH 

II  II 
7CH,          CH2                 CH2  CH2 

II  II 

/3CH2+0 = CH0H+50  -  COOH      COOH 

I  ! 

aCH2  CH2  2C02 

I  I 

COOH      COOH  2H20 

In  presenting  the  theory  of  beta-oxidation  refer- 
ence has  been  made  to  the  straight  chain  fatty  acids 


T6  DIABETES  MELLITUS 

only.  Acids  with  branched  chains  behave  somewhat 
differently.  Normal  valerianic  (C5Hi0O2)  acid  is 
not  ketogenic,  iso-valerianic  acid  is  ketogenic.  The 
reactions  for  each  may  be  written  as  follows : 


CH3              CHj 

1                    1 

CH3 

j 

I                    1 
CH2             CHj 

1                   1 

CH,+H2o-}-co, 

/SCH2+Or->  CHOH-f-50->COOH 

1                   1 

CH,            CH2 

1 

Propionic  acid 

COOH        COOH 

Normal 
valerianic  acid 

CHj        CH, 

\    / 

/3CH,                + 

1 

0 

CH, 

1 
->        CHOH 

CH, 

1 

CH, 

1 

COOH 

COOH 

Iso-valerianic  acid 

Also  it  is  apparent  that  only  one  molecule  of  buty- 
ric acid  can  be  derived  from  each  molecule  of  a  higher 
fatty  acid.  Fatty  acids  with  an  uneven  number  of 
carbon  atoms  are  not  found  in  the  fats  of  the  animal 
body.  Butyric  acid  may  be  derived  then  from  all  the 
fats  of  the  tissues  and  food. 

From  the  results  of  experiments  with  butyric  acid 
it  can  hardly  be  doubted  that  oxidation  takes  place 
with  the  formation  of  diacetic  acid  primarily  and  that 
the  £-hydroxybutyric  acid  is  secondary  to  a  reduction 
of  the  diacetic.  The  possible  results  may  be  repre- 
sented as  follows: 


ACIDOSIS  77 

CH,.CH2.CH2.COOH  \ 
CH,.CO.CH2.COOH  <=*   CH3.CHOH.CH2.COOH 
^^CHs.COOH 

It  is  not  possible  to  be  in  the  least  dogmatic  regard- 
ing the  pathological  steps  until  our  knowledge  of  the 
normal  is  more  complete.18 

Since,  however,  but  one  molecule  of  butyric  acid 
can  proceed  from  a  given  fatty  acid  there  is  a  prac- 
tical advantage  to  the  diabetic  with  acidosis  in  using  a 
higher  fat  rather  than  a  lower.  For  example,  in  butter 
the  butyric  acid  is  at  once  converted  by  the  first  oxida- 
tion into  oxybutyric  acid  and  very  little  energy  is 
liberated  in  this  transformation,  whereas  with  the 
higher  fatty  acids  there  is  a  succession  of  oxidative 
steps  each  liberating  energy  before  the  butyric  is 
finally  derived. 

In  the  transformation  of  amino-acids,  the  cleavage 
products  of  protein,  into  ketone  bodies  there  is  no  de- 
parture from  the  principles  already  set  forth.  The 
presence  of  the  amino  group  (NH2)  determines  in  the 
first  instance  to  which  carbon  atom  the  oxygen  is 
joined  and  hence  the  position  of  the  initial  cleavage 
in  the  molecule;  thence  the  reaction  proceeds  as  al- 
ready detailed. 

16  For  a  concise  presentation  of  the  chemical  aspects  of  fatty  acid 
oxidation  see  Dakin:  Oxidations  and  Reductions  in  the  Animal  Body. 
New  York,  1912. 


CH, 

I 
CHa 


78  DIABETES  MELLITUS 

CH, 

I 

CHa  CHj  CH, 

I  I  ! 

CHa  CHa  /8CH2  CHOH 

I  III 

CH.NH2+ H20~>  CHOH+02  =  CH2  +  O  =  CH, 

I  III 

COOH  COOH  COOH  COOH 

NH,  H20+C02 

a-amino-valer-  Hydroxy-val-  Butyric  acid       j3-oxybutyrie 

ianic  acid  erianic  acid  acid 

The  reaction  for  leucine  (a  amino-isobutyl  acetic 
acid)  is  as  follows: 


CH,             CH3 

\      / 
CH 

CH,             CH, 

\      / 
CH 

1 

CH3              CH, 

\      / 
/SCH 

CH, 

1 
CO 

CH2+H20 

1 

-*      CH2+Oa 

1 

— > 

CH2+0  — 

1 

►     CHa 

aCHNH2 

j 

choil 

COOH 

COOH 

COOH 

COOH 

Leucine 

NH, 

a-hydroxy-isob  utyl 
acetic  acid 

Iso-valerianic 
acid 

Diacetic 
acid 

The  relative  amounts  of  ketone  bodies  in  the  urine 
derivable  from  protein  and  fat  respectively  cannot  be 
definitely  stated,  but  as  only  a  few  of  the  amino-acids 
composing  protein  are  convertible  into  ketones  the 
amount  from  this  source  is  probably  small.  The  pre- 
dominant factor  is  the  fat.19 

Are  then  the  ketone  bodies  to  be  regarded  as  prod- 
ucts of  normal  metabolism  which  in  consequence  of 
some  cellular  disturbance  have  escaped  the  final  steps 
of   disintegration?     The   perfusion   experiments    of 

18  If  all  the  fatty  acid  were  converted  to  j3-oxybutyric  acid,  100 
grammes  of  fat  would  yield  36  grammes;  100  grammes  of  protein  prob- 
ably not  over  20  grammes. 


ACIDOSIS  79 

Embden  would  indicate  this  to  be  the  case,  qualita- 
tively at  least,  since  it  is  hardly  probable  that  the  con- 
ditions of  their  experiment  institute  an  activity  in  the 
liver  that  is  wholly  pathological.  Nor  is  it  inconceiv- 
able that  the  large  amounts  of  0-oxybutyric  acid  ex- 
creted in  the  urine  by  patients  in  diabetic  coma,  100  to 
150  grammes  per  day,  could  be  under  normal  condi- 
tions completely  burned.  Normal  dogs  can  metab- 
olize 2  to  3  grammes  of  £-oxybutyric  acid  per  kilo  body 
weight  per  day  and  of  diacetic  acid  much  more.  If 
then  it  be  assumed,  as  many  believe,  that  the  ketone 
bodies  represent  only  interrupted  oxidation,  at  what 
step  does  this  disturbance  occur?  It  has  been  shown 
that  either  aceto- acetic  or  0-hydroxybutyric  acids  are 
logical  links  in  the  oxidation  of  fatty  acids;  and  it 
seems  quite  probable  that  each  is  formed  from  differ- 
ent precursors  and  as  soon  as  formed  undergoes  oxi- 
dation to  lower  fatty  acids,  such  as  acetic  and  formic. 

CHYCO.CHYCOOH      +H20=CHS.C00H+CH3.C00H 
CH8.CH0H.CH2.C00H-f-     0  =  CH3.C00H+CH3.C00H 

Under  these  circumstances,  only  when  conditions  for 
oxidation  failed  would  these  acids  accumulate  and  ap- 
proach a  state  for  equilibrium  of  transformation  one 
to  the  other. 

In  the  course  of  testing  various  substances  to  de- 
termine whether  they  may  be  transformed  into  ketone 
bodies  it  was  noted  that  some  substances  inhibit  ketone 


80  DIABETES  MELLITUS 

formation  in  perfusion  experiments  and  in  the  diabetic 
organism.  This  class  of  compounds  is  spoken  of  as 
antiketogenic.  Chief  among  these  substances,  at  least 
for  the  normal  organism,  are  the  carbohydrates  and, 
as  Hirschfeld  demonstrated,  also  protein  when  it  is 
ingested  in  large  amounts.  In  one  experiment  a 
marked  ketonuria  incident  to  an  exclusively  protein 
diet  which  was  equivalent  to  from  20  to  27  grammes 
nitrogen  per  day,  vanished  when  the  ingest  was  in- 
creased up  to  30  to  40  grammes  of  nitrogen. 

In  the  experiments  conducted  by  perfusing  liver, 
with  diabetic  men  and  with  phlorhizinized  dogs  the  re- 
sults secured  are  not  always  clear  cut  nor  concordant. 
Of  the  amino-acids,  glycocoll,  alanine,  glutamic  and 
aspartic  acids  are  antiketogenic  (Baer  and  Blum,20 
Borschardt),  possibly  because  they  may  be  trans- 
formed into  sugar;  the  results  with  acetic  and  lactic 
acids  are  conflicting. 

With  diabetic  patients  Neubauer 21  has  shown  a 
decided  reduction  in  the  urinary  ketone  bodies  follow- 
ing the  ingestion  of  alcohol.  Aicohoi 

1st    id    3d   4th 
day    day   day   day 

Acetone 1.08     0.58    0.91     2.4 

/3-oxybutyric 6.90    2.50     3.10     8.2 

Hirschfeld  found  no  change  in  the  urine  of  a  normal 
man  after  the  use  of  alcohol. 

20  Baer  and  Blum:  Hofm.  Beitr.,  1907,  io,  p.  80;  n,    p.  101. 

21  Neubauer:  Munch,  med.  Wochenschr.,  1906,  53,  p.  791. 


ACIDOSIS  81 

Of  the  other  substances  that  influence  the  acid  pro- 
duction in  normal  persons  many  are  not  of  use  with 
diabetics  or  the  observed  results  have  not  been  uni- 
form. Glycocoll  is  clearly  antiketogenic  in  some  in- 
stances (Hirschfeld) ,  but  large  amounts  are  required, 
40  to  60  grammes.  With  xylose,  inosite,  citric  acid, 
and  glucosamine  the  effect  is  not  definite.  Those  sub- 
stances which  are  most  efficient  in  reducing  the  keto- 
nuria  of  normal  persons,  carbohydrates  and  protein 
(since  it  is  converted  into  sugar  in  the  organism)  are 
of  no  effect  with  severe  diabetes,  while  on  the  other 
hand,  alcohol  which  is  inoperative  with  normal  man  is 
antiketogenic  with  many  severe  diabetics. 


V 


PATHOGENESIS 

The  immediate  cause  of  glycosuria  may  be  either 
( 1 )  an  increased  permeability  of  the  kidney  to  normal 
concentrations  of  sugar  in  the  blood,  (2)  the  blood 
sugar  may  be  so  changed  in  its  physiochemical  state 
that  it  passes  through  the  renal  filter,  or  (3)  the  blood 
sugar  may  be  increased  above  the  powers  of  the  kidney 
to  retain  it. 

The  first  condition  is  that  of  renal  diabetes  in 
which  the  blood  sugar  is  normal.  It  is  supposed  at 
present  that  the  glycosuria  here  depends  upon  an  ab- 
normal permeability  of  the  kidney  to  the  sugar  in  the 
blood.  The  peculiarities  of  renal  diabetes  are  dis- 
cussed elsewhere.  It  seems  possible  that  there  is  also  a 
renal  element  in  true  diabetes,  since  the  glycosuria  is 
often  of  a  more  pronounced  degree  than  is  explicable 
by  the  hyperglycemia.  With  non-diabetics  the  in- 
crease in  the  blood  sugar  attendant  upon  fever  is  but 
seldom  manifested  in  glycosuria.  On  the  other  hand, 
many  diabetics  excrete  sugar  at  times  when  the  blood 
sugar  is  very  slightly,  if  any,  above  the  normal  bounds. 
This  is  the  evidence  commonly  cited  in  favor  of  a  renal 
element  in  true  diabetes.  The  glycosuria  under  these 
conditions  can  be  explained  as  well  by  assuming  a 

82 


PATHOGENESIS  83 

change  in  the  state  of  the  blood  sugar  as  by  postulat- 
ing an  increase  in  renal  permeability.  This  doctrine 
is  based  upon  the  idea  that  the  blood  sugar  normally 
exists  in  some  combined  state  with  either  protein,  a 
lipoid,  or  some  such  substance;  and  in  consequence  of 
this  combination  there  is  no  diffusion  normally 
through  the  renal  epithelium.  In  the  diabetic  the 
sugar  is  assumed  to  be  uncombined  and  hence  dif- 
fusible. In  other  words,  normally  the  sugar  exists  in 
a  colloidal  state,  in  diabetes  as  a  crystalloid.  This 
conception  is  not  new  and  in  one  form  or  another  has 
been  supported  by  the  majority  of  students  of  dia- 
betes. What  then  is  the  objection  that  may  be  brought 
against  the  hypothesis?  Simply  that  the  combined 
state  cannot  be  demonstrated.  The  careful  and  well 
planned  experiments  of  Rona  failed  to  indicate  either 
by  methods  of  dialysis  or  by  using  collodial  precipi- 
tants  that  the  blood  sugar  is  combined.  As  there  are 
inherent  objections  to  any  known  physicochemical 
means  for  the  solution  of  the  problem  because  of  the 
possible  delicacy  of  equilibrium  of  the  substances  in 
blood,  the  possibility  still  remains  that  the  normal  blood 
sugar  exists  in  a  colloidal  state.  When  considerable 
amounts  of  sugar  are  given  to  normal  animals  or  man, 
either  by  mouth  or  subcutaneously,  there  is  no  diuresis 
even  though  some  sugar  be  secreted  into  the  urine, 
while  with  diabetes  there  is  a  diuresis  proportionate  to 


84  DIABETES  MELLITUS 

the  sugar  loss.  Diuresis  also  results  from  introduc- 
ing sugar  solutions  directly  into  the  circulation  of  nor- 
mal animals,  and  from  these  facts  Allen  *  concludes 
that  the  blood  sugar  is  normally  in  a  combined  state. 
The  hypothesis  is  alluring  but  cannot  be  subscribed  to 
on  the  facts  at  present  available. 

The  third  possible  cause  of  glycosuria,  increase 
in  the  amount  of  blood  sugar,  is  observed  with  the 
great  majority  of  diabetics  and  this  increase  has  gener- 
ally been  conceived  as  the  immediate  occasion  for 
sugar  excretion  in  the  urine.  This  increase  is  often  of 
a  degree  that  could  hardly  be  retained  by  a  normal 
kidney  and  it  is  not  then  necessary  to  postulate  an  in- 
crease of  renal  permeability.  What  then  are  the 
causes  of  the  hyperglycemia?  There  are  three  which 
appear  possible:  (1)  Overproduction  of  sugar,  (2) 
failure  to  warehouse  sugar  that  is  formed,  (3)  failure 
of  the  cells  to  utilize  sugar. 

The  overproduction  of  glucose  takes  place  in  some 
of  the  experimental  glycosurias,  notably  with  piqure, 
and  is  dependent  upon  the  glycogen  deposits  in  the 
body.  If  there  is  no  glycogen  available  there  is  no 
resultant  hyperglycemia  nor  glycosuria  and  the  latter 
ceases  when  the  glycogen  is  exhausted.  Conceivably 
the  glycosurias  following  injuries,  i.e.,  fracture  of  the 
skull,  are  of  this  nature.    Von  Noorden  has  expressed 

1  Glycosuria,  p.  303. 


PATHOGENESIS  85 

the  opinion  that  overproduction  or  abnormal  produc- 
tion is  a  large  factor  in  the  diabetic  state.  For  this 
doctrine  there  is  no  basis,  since  all  the  sugar  excreted 
is  readily  accounted  for.  Other  than  glycogen  the 
only  known  source  of  sugar  in  the  body  is  protein  and 
all  evidence  goes  to  show  that  the  glucose  production 
from  protein  is  normally  at  its  maximum.  For  von 
Noorden's  belief  in  the  transformation  of  fatty  acids 
into  sugar  there  is  no  evidence.  Hence  there  can  be 
no  overproduction  of  sugar  in  a  qualitative  sense.  If 
the  substances  which  form  sugar  undergo  this  change 
more  rapidly  in  the  diabetic  organism  than  in  health 
(if  the  overproduction  is  purely  quantitative),  then 
the  fact  would  be  disclosed  in  other  metabolic  relations 
(i.e. j  nitrogen  metabolism),  which  is  not  the  case.  It 
matters  not  whether  the  stimulus  come  to  the 
liver  direct  or,  as  von  Noorden  believes,  through  a 
complex  relation  of  the  chromaffin  system,  the  hy- 
perglycemia depending  on  liver  deposits  must  fall 
when  these  deposits  are  diminished  as  in  severe  dia- 
betes. In  these  very  instances  the  sugar  output  is  larg- 
est and  the  ability  to  store  glycogen  most  impaired. 

The  overproduction  theory  of  diabetes  of  the  von 
Noorden  school  rests  to  a  large  extent  on  the  experi- 
ments of  Porges  and  Salomon  2  who  found  that  liga- 
tion of  the  abdominal  aorta  and  inferior  vena  cava  in 

a  Biochem.  Zeit,  1910,  xxvii,  pp.  131,  143. 


86  DIABETES  MELLITUS 

rabbits  and  depancreatized  dogs  causes  a  rise  in  the 
respiratory  quotient.  They  interpreted  this  to  indi- 
cate that  (1)  the  organism  depends  on  the  liver  for 
ability  to  burn  protein  and  fat,  and  (2)  depancreatized 
animals  retain  the  power  to  burn  sugar.  Murlin  3  has 
shown  that  under  the  conditions  of  the  above  experi- 
ment the  changes  in  respiratory  quotient  are  due  to 
changes  in  the  mechanical  factors  of  circulation  and 
that  the  metabolism  is  not  changed. 

The  severe  diabetic  manifests  a  failure  both  to 
warehouse  sugar  and  to  utilize  sugar.  Normally,  in- 
gested sugar  is  stored  either  as  glycogen  or  as  fat  and 
the  ability  to  do  this  is  practically  unlimited.  Even 
when  very  large  amounts  of  glucose  are  ingested  and 
there  is  an  escape  of  some  into  the  urine  the  amount 
lost  is  but  a  small  fraction  of  the  total  ingested.  And 
this  may  be  continued  indefinitely ;  indeed,  with  those 
individuals  who  indulge  excessively  in  starchy  and 
sweet  foods,  is  continued  for  years,  illustrating  thereby 
the  ability  of  the  healthy  organism  to  store  up 
surplus  carbohydrate.  On  the  other  hand,  where 
sugar  is  ingested  by  persons  with  severe  diabetes  it  is 
excreted  quantitatively  in  the  urine.  There  is  neither 
ability  to  store  this  sugar  as  glycogen  and  fat  nor  to 
utilize  it  for  energy.  That  the  ability  to  utilize  glu- 
cose is  lost  is  also  disclosed  by  the  respiratory  quo- 

8  Jour.  Biol.  Chem.,  1913,  16,  p.  79. 


PATHOGENESIS  87 

tient4  which  with  these  cases  is  low,  indicating  the 
combustion  of  protein  and  fat.  Failure  of  the  cells  to 
make  use  of  the  sugar  presented  to  them  is  equivalent 
in  effect  to  starvation.  Normally  when  the  organism 
requires  sugar  there  is  a  responding  production  in 
sugar  formation  from  the  glycogen  stores  and  this  for- 
mation continues  so  long  as  there  is  demand.  In  dia- 
betes the  demand  is  continuous  from  the  cells  and  be- 
cause there  is  no  utilization  and  a  constant  demand  the 
blood  sugar  rises.  In  this  sense  and  this  only  is  there 
any  overproduction  of  sugar. 

Finally,  why  is  the  diabetic  organism  unable  to 
utilize  carbohydrate?  Evidently  this  is  not  an  im- 
pairment of  oxidation,  since  in  this  respect  the  dia- 
betic appears  normal.  Several  theories  have  been  ad- 
vanced but  the  question  is  yet  open.  Here  again  the 
question  reverts  primarily  to  the  state  of  the  blood 
sugar.  The  older  conception  postulated  an  abnormal 
combination  of  the  blood  sugar  in  consequence  of 
which  the  cells  were  not  able  to  become  "  fixed  "  to  the 
sugar  ( Schmiedeburg,  Seegen,  Naunyn).  As  a  re- 
sult of  the  pancreatic  theory  of  diabetes  Minkowski 
saw  two  possible  actions  of  an  internal  secretion :  ( 1 ) 
action  on  the  sugar  preparing  it  for  cleavage;   (2) 

*  When  sugar  is  administered  to  depancreatized  dogs  the  respiratory 
quotient  does  not  rise  as  it  does  with  normal  dogs,  indicating  that  the 
sugar  is  not  burned;  Veyzar  and  Fejes:  Biochem.  Zeitschr.,  1913,  53, 
140;  Murlin  and  Kramer:  Jour.  Biol.  Chem.,  1913,  xv,  365. 


88  DIABETES  MELLITUS 

action  on  the  cells.  A  third  hypothesis  has  been  advo- 
cated; namely,  that  an  antagonistic  substance  is  nor- 
mally destroyed  by  the  pancreatic  internal  secretion 
(toxic  theory) .  In  diabetes  the  pancreas  fails  to  effect 
destruction  and  as  a  result  combustion  of  sugar  is  in- 
hibited. These  ideas  are  based  upon  a  conception  of 
blood  sugar  normally,  in  some  combination;  patho- 
logically, free  or  joined  in  an  abnormal  compound. 
The  most  insistent  advocate  of  this  doctrine  was  Pavy. 

The  recent  application  of  Ehrlich's  side-chain 
theorv  to  the  whole  domain  of  cell  activities  has  found 
its  expression  in  relation  to  diabetes  in  Allen's  hy- 
pothesis of  a  pancreatic  amboceptor.  The  Ehrlich 
conception  of  the  utilization  of  foods  by  the  cells  is 
that  the  nutrient  material  must  first  become  fixed  to 
the  cell  before  it  can  be  oxidized  in  the  same  manner 
as  the  complement  is  fixed  to  the  cells  through  the 
mediation  of  an  amboceptor.  The  application  of  the 
theory  to  diabetes  supposes  an  amboceptor  normally 
supplied  by  the  pancreas  to  be  lacking  in  the  disease 
state  and  in  default  of  amboceptor  the  cells  are  unable 
to  "fix"  and  to  utilize  sugar. 

No  theory  thus  far  advanced  is  adequate  to  ex- 
plain all  the  phenomena  observed  with  human  diabetes, 
nor  does  any  theory  at  present  rest  on  a  broad  basis  of 
demonstrated  fact.  These  hypotheses  must  be  held 
purely  in  the  scientific  spirit  of  a  working  basis  for 
experiment. 


VI 

HISTORY 

The  earliest  reference  that  may  be  construed  as 
alluding  to  diabetes  is  the  polyuria  mentioned  in  the 
papyrus  Ebers.  Celsus  speaks  of  a  disorder  remark- 
able for  the  increase  in  the  amount  of  urine  and  lead- 
ing to  emaciation.  It  seems  rather  surprising  that  a  dis- 
ease so  clearly  defined  made  no  recordable  impression 
on  the  Greeks,  yet  no  mention  is  found  in  the  texts 
that  have  come  down  to  us  earlier  than  the  writings  of 
Aretaeus,  150  a.d.  Like  Galen,  his  contemporary,  he 
dwells  upon  the  polyuria  and  the  abnormal  thirst. 
Aretasus  first  gave  the  name  "diabetes"  (  hia^alveiv  ) 
to  the  disorder  on  account  of  his  conception  of  the  dis- 
ease as  a  transudation  of  the  liquid  ingesta  and  fluids 
of  the  body  into  the  urine.  To  the  kidneys  Galen 
assigned  the  cause  of  abnormal  diuresis  ( diarrhoea  per 
urinas)  and  this  view  prevailed  throughout  the  middle 
ages.  A  somewhat  different  interpretion  of  the  dis- 
ease was  given  by  Paracelsus  in  attributing  to  an  ab- 
normal salt  formation  the  causes  of  renal  activity. 
This  notion  of  a  morbid  state  of  the  blood  was  en- 
larged upon  independently  by  Sylvius,  father  of  the 
iatrochemical  school  {Opera  med.,  Amstelodami, 
1680). 


90  DIABETES  MELLITUS 

Until  the  latter  part  of  the  seventeenth  century 
European  physicians  never  suspected  that  the  urine  in 
this  disease  contained  sugar.  If  it  were  not  then  for 
the  other  characteristic  symptoms  referred  to  in  the 
earlier  writings  we  should  be  left  in  doubt  whether  the 
disorder  described  were  diabetes  mellitus  or  insipidus. 
But  according  to  the  Ayur  Veda  (500  a.d.)  the 
saccharine  nature  of  diabetic  urine  had  been  known  to 
Hindu  physicians  from  remote  times,  and  undoubtedly 
diabetes  mellitus  is  alluded  to  in  the  fifth  century  in 
the  description  of  a  disease  characterized  by  "honey 
urine."  European  medicine  was  enlightened  by  Willis 
in  1674,  and  from  then  on  diabetes  was  differentiated 
as  saccharine,  and  non-saccharine;  but  not  till  a  cen- 
tury later  was  sugar  demonstrated  in  the  urine  by 
Dobson  and  the  disease  recognized  as  a  clinical  entity. 
Dobson  conjectured  that  the  blood  of  diabetic  patients 
contains  sugar  and  Rollo  concurred  in  this  supposition 
by  reason  of  the  diminished  tendency  to  putrefaction. 
Many  chemists  made  fruitless  attempts  to  detect  blood 
sugar,  which  was  finally  demonstrated  by  an  apothe- 
cary,  Ambrosian,  in  1835.  I  Instead  of  elucidating  the 
cause  of  the  disorder,  these  new  facts,  even  as  to-day, 
made  the  essential  cause  but  more  vague  and  intangi- 
ble. Many  and  curious  theories  were  advanced,  flour- 
ished for  a  day,  and  were  forgotten.  Some  believed 
the  fault  to  be  essentially  digestive  in  that  the  starchy 


HISTORY  91 

foods  are  too  rapidly  converted  into  sugar  '( Bouchar- 
dat) ,  while  others  recognized  the  cause  in  a  diminished 
alkalinity  of  the  blood.  No  theory  had  a  basis  until 
Claude  Bernard  published  his  experiments  upon  the 
relation  of  the  liver  to  sugar  formation  (1848)  and 
upon  piqure  glycosuria  (1850).  These  experiments 
of  Bernard  opened  up  paths  of  investigation  which  are 
yet  being  followed  by  physiologists  and  pathologists. 

Proportionate  to  the  scientific  knowledge  of  dia- 
betes its  therapy  was  precocious.  Shortly  after  Dob- 
son  demonstrated  sugar  in  diabetic  urine  another 
Englishman,  John  Rollo,  pointed  out  the  deleterious 
effects  of  carbohydrate  diet.  Rollo  introduced  the 
meat  diet  in  the  treatment  of  diabetes  and  the  results 
observed  by  this  method  influenced  at  the  time,  to  no 
little  degree,  the  pathological  theories  of  the  disorder. 
No  important  advances  were  made  upon  Rollo's 
method  until  the  latter  part  of  the  last  century. 

That  severe  cases  of  diabetes  were  liable  to  die  in  a 
peculiar  form  of  coma  has  been  known  for  more  than  a 
century,  but  to  Kussmaul  (1877)  in  Germany  and  to 
Sir  Walter  Foster  in  England  we  owe  a  careful  de- 
scription of  its  features. 


VII 

ETIOLOGY 

The  incidence  of  diabetes  as  estimated  by  mean 
mortality  statistics  indicates  that  the  disease  is  not 
common.  For  those  countries  of  western  Europe 
wherein  vital  statistics  are  most  carefully  recorded, 
there  are  annually  five  deaths  from  diabetes  per 
100,000  population.  The  registration  area  of  the 
United  States  and  the  larger  cities  indicates  an  annual 
mean  mortality  of  12.6  per  100,000  living  persons. 
Within  these  areas,  however,  there  is  noted  a  great 
variation  in  the  figures  which  is  most  striking  in  com- 
paring large  cities.  In  Helsingfors  the  average  is  5, 
while  in  Copenhagen  it  is  15;  in  Berlin  20,  Paris  14, 
London  7.  The  lowest  mortality  per  100,000  popula- 
tion appears  to  be  in  Hong  Kong,  0.15,  and  the 
highest  in  Malta,  37.8.  Within  the  United  States  the 
mortality  in  the  larger  cities  varies  widely;  in  Boston  it 
is  16.1 ;  Chicago,  11.1 ; x  New  Orleans,  8.5;  New  York, 
15.1  ;*  St.  Louis,  12.9;  San  Francisco,  15.1  These 
figures  can  hardly  be  taken  at  face  value,  due  to  the 
inherent  defects  in  all  modes  of  classification.  It  is 
probable,  however,  that  the  frequency  of  the  disease 
is  under-  rather  than  overrated;  many  cases  doubtless 

1  Data  kindly  furnished  by  the  Health  Officers  of  these  cities. 
92 


ETIOLOGY  93 

escape  detection  in  the  absence  of  urine  examinations. 
Taken  roughly  these  statistics  may  indicate  the  fre- 
quency of  diabetes  in  large  masses  of  population.  It 
is  the  belief  of  some  authors  that  diabetes  is  becoming 
more  frequent  and  the  cause  assigned  for  this  is  the 
increase  of  wealth  and  consequent  indulgence  to  the 
palate.  It  cannot  be  overlooked  that  methods  of  diag- 
nosis are  becoming  all  the  time  more  generally  used 
than  heretofore,  and  that  diseases  are  now  detected 
where  formerly  no  diagnosis  was  attempted.  An  in- 
crease in  the  frequency  of  many  maladies  might  be 
cited  where  the  explanation  is  solely  that  a  diagnosis 
is  made.  It  is  possible,  as  some  assert,  that  diabetes  is 
more  frequent  than  half  a  century  ago  but  better  evi- 
dence is  required  to  establish  the  fact. 

It  has  long  been  a  tradition  that  certain  races  are 
more  susceptible  than  others  to  this  disease,  and  the 
Jews  are  commonly  cited  as  an  example.  Of  400  cases 
in  Frerichs'  series,  102  were  Jews.  The  susceptibility 
of  the  Hebrews  is  best  attested  by  the  careful  survey 
of  Frankfurt  a.M.  by  Wallach 2  who  found  that  the 
proportion  of  deaths  from  diabetes  to  the  total  deaths 
from  all  other  causes  was  six  times  greater  among  the 
Jews  than  among  the  other  inhabitants.  It  was  shown 
also  that  the  mortality  3  from  diabetes  among  the  Jews 

8  Deut.  med.  Wochenschr.,  1893. 

3  Williamson:  Diabetes  Mellitus,  London,  1898,  p.  100. 


94  DIABETES  MELLITUS 

was  greater  at  all  ages.  Likewise  the  Hindus  in 
India  are  said  to  suffer  more  from  the  malady  than  the 
other  races.  In  America  most  authors  agree  that  rela- 
tively few  cases  are  found  among  the  colored  race. 
This  statement  is  not  demonstrable  by  available  statis- 
tics. The  vital  statistics  of  the  United  States  Govern- 
ment show  the  frequency  of  diabetes  as  a  cause  of 
death  in  the  white  and  colored  races  per  100,000  popu- 
lation as  abstracted  for  three  of  the  states. 

Connecticut .19.9  white,  6.0  colored. 

Maryland 14.4  white,  4.7  colored. 

Michigan 14.8  white,  12.0  colored. 

The  available  statistics  in  America  and  particu- 
larly in  Europe  leave  but  little  room  for  doubt  that 
social  status  is  an  important  factor  in  the  incidence  of 
diabetes.  It  is  particularly  among  the  well-to-do 
classes  that  the  highest  percentages  of  cases  are  found. 
Even  with  Hebrews  it  is  chiefly  the  rich  who  are  af- 
flicted ;  among  the  poor  there  is  usually  only  a  slightly 
increased  percentage  over  the  other  members  of  a 
community.  Bertillon 4  has  shown  that  the  mortality 
from  diabetes  in  Paris  is  higher  in  all  those  arrondisse- 
ments  where  the  inhabitants  are  wealthy.  It  is  not 
easy  to  select,  out  of  the  possible  causes  that  riches 
may  contribute,  the  important  factor;  besides  overin- 

4  Bertillon:  De  la  frequence  des  principales  maladies  &  Paris  pendant 
la  periode  1865-1887,  Paris,  1889. 


ETIOLOGY  95 

diligence  in  foods,  the  wealthy  man  often  takes  too 
little  exercise,  and  very  often  he  carries  large  responsi- 
bilities which  entail  constant  nervous  tension.  The 
fact  that  women  are  somewhat  less  disposed  to  dia- 
betes than  men  suggests,  perhaps,  the  importance  of 
the  nervous  strain  of  modern  city  life  as  a  contribut- 
ing cause,  especially  among  the  rich.  According  to 
the  United  States  Census  mortality  statistics  of  the 
140  classified  occupations,  the  percentage  of  deaths 
due  to  diabetes  is  highest  among  lawyers,  clergymen, 
and  commercial  travellers. 

An  inherited  predisposition  to  diabetes  is  well 
attested  by  a  number  of  remarkable  cases  recorded  in 
the  literature.  Morton  first  called  attention  to  this 
fact  in  1696.  Von  jSToorden  and  Pleasants  5  have  each 
recorded  a  family  in  which  one  or  more  members  in 
each  generation  were  affected.  There  are  also  a  num- 
ber of  instances  where  two  or  more  children  in  a  f amilv 
have  succumbed  to  diabetes.  I  have  reported  a  family 
of  four  children  all  of  whom  became  diabetic  between 
the  ages  of  six  and  seventeen  years.6  In  an  analysis 
of  cases  of  this  kind  there  is  not  always  a  history  of 
diabetes  in  the  parents ;  it  is  often  noted,  however,  that 
there  is  a  neuropathic  taint  in  the  family.     Naunyn 

5 Von   Noorden:   Zuckerkrankheit,   Berlin,   1907,  p.   45.     Pleasants: 
Johns  Hopkins  Hospital  Bulletin,  1900,  n,  p.  325. 

e  Foster:  Johns  Hopkins  Hospital  Bulletin,  1912,  23,  p.  54. 


96  DIABETES  MELLITUS 

took  especial  care  to  secure  data  and  found  that  in  31 
per  cent,  of  201  cases  there  was  a  history  of  diabetes 
in  some  relative.  Fritz  and  Joslin  observed  this  fact 
in  23.8  per  cent,  of  their  cases.  An  inherited  tendency 
was  noted  by  Lion  7  in  62  per  cent,  of  18  diabetic 
children  where  the  family  history  was  known. 

A  curious  hereditary  relation  which  diabetes 
mellitus  sometimes  bears  to  diabetes  insipidus  should 
be  mentioned.  Diabetes  mellitus  in  a  parent-  and  dia- 
betes insipidus  in  one  of  the  children  was  reported  by 
Senator ; 8  and  there  are  a  few  cases  recorded  where 
diabetes  insipidus  has  occurred  in  some  member  of  a 
diabetic  family.  The  relation  of  the  two  diseases  is 
further  suggested  by  non-saccharine  diabetes  being 
succeeded  by  glycosuria.  Some  of  these  cases  are 
supposed  to  have  regained  perfect  health. 

Diabetes  is  commonly  believed  to  occur  more  often 
with  men  than  with  women.  When,  however,  large 
numbers  of  cases  are  collected  there  seems  to  be  some 
doubt  as  to  the  accuracy  of  this  generalization.  The 
following  table  from  the  Mortality  Statistics,  Bureau 
Census,  1909,  p.  588,  indicates  the  relation  of  the  dis- 
ease to  sex  and  the  frequency  during  various  periods 
of  life.    It  is  most  common  after  forty  and  is  a  rare 


7  Lion  and  Moreau:  Arch,  de  Med.  des  Infant's,  1909,  xn,  p.  21. 
"Senator:  Deutsch.  med.  Wochensehr.,  1897,  June  10. 


ETIOLOGY  97 

disease  before  twenty,  although  no  age  is  exempt.    It 
has  been  noted  in  new-born  infants. 

Years  Male  Female  Years  Male  Female 


...  38 

45 

40-49 

. ...  345 

354 

5-9 

...  51 

65 

50-59 

. ...  592 

703 

10-14  

...  68 

107 

60-69 

, ...  760 

950 

15-19  

...  113 

71 

70-79 

456 

527 

20-29  

...  205 

161 

80-89 

...  118 

108 

30-39  

...232 

187 

90 

...   9 

3 

In  Germany  much  emphasis  is  placed  upon  the 
association  of  obesity  with  diabetes.  That  relation 
seems  to  me  much  less  striking  in  America  than  in 
Germany.  In  hospital  service  here  the  diabetic  who 
is  or  has  been  overweight  is  the  exception  and  of  the 
obese  cases  in  my  private  practice  nearly  all  have  been 
Hebrews. 

There  is  a  form  of  alimentary  glycosuria  which  I 
have  encountered  so  frequently  in  association  with 
gout  that  I  have  come  to  regard  it  as  somewhat  charac- 
teristic of  that  disease.  I  refer  to  that  form  of  alimen- 
tary glycosuria  which  manifests  itself  in  the  urine 
voided  after  dinner  while  during  the  remainder  of  the 
day  there  is  no  sugar  excreted.  It  will  be  found  with 
these  persons,  usually  men  of  robust  physique  who 
have  had  one  or  more  attacks  of  gout,  that  if  the  urine 
voided  during  the  six  hours  after  dinner  be  saved 
separately  from  the  rest  of  the  twenty-four  hour  col- 
lection this  will  contain  a  small  amount  of  sugar 


98  DIABETES  MELLITUS 

while  the  remainder  will  not.  This  fact  simply  indi- 
cates an  excessive  consumption  of  starches  (and 
sweets )  at  one  meal  and  a  lowered  tolerance.  Some  of 
these  cases  ultimately  become  true  diabetics.  I  have 
seen  two  cases  of  mild  diabetes  that  I  had  studied 
some  years  previously  as  cases  of  gout  and  had  then 
observed  the  alimentary  glycosuria  referred  to. 

A  small  percentage  of  the  cases  of  diabetes  may 
be  traced  to  some  immediate  etiological  factor.  Thus 
there  are  instances  where  glycosuria  has  been  first 
noted  after  acute  infections,  influenza,  tonsillitis,  and 
syphilis.  A  number  of  cases  have  dated  from  severe 
injuries.  Ebstein  analyzed  the  cases  of  "traumatic 
diabetes"  and  found  that  half  of  these  had  received  in- 
juries to  the  head.  The  relation  of  transitory  sugar 
excretion  to  fracture  of  the  skull  is  mentioned  in  the 
chapter  on  Pathology. 

Emotional  influences  have  been  held  accountable 
for  many  cases  of  diabetes  since  Willis  commented 
that  the  disorder  followed  "  sadness  or  long  sorrow." 
Some  examples  of  the  coincidence  between  the  onset 
and  emotional  disturbances  are  remarkable.  A  well- 
known  case  is  that  of  an  officer  who  acted  as  second 
for  a  friend  who  was  killed  in  a  duel.9  During  the 
ensuing  two  months  the  officer  became  much  depressed 
and  lost  weight  and  it  was  discovered  that  he  was  suf- 

8Seegen:  Der  Diabetes  Mellitus,  Leipzig,  1870,  p.  64. 


ETIOLOGY  99 

fering  from  diabetes.  Dickinson  10  records  a  somewhat 
similar  case  of  a  mother  who  saw  her  child  fall  from  a 
third-floor  window.  It  was  at  first  supposed  that  the 
child  was  mortally  injured,  but,  although  it  survived, 
the  mother  was  unable  to  eat  or  sleep  for  three  weeks 
after  the  accident.  Shortly  after  she  developed  ex- 
cessive thirst  and  died  of  diabetes  within  ten  months. 
There  are  many  other  cases  scattered  through  the 
literature. 

A  boy  four  years  old  was  brought  to  me  with  the 
history  that  the  child  had  been  in  a  runaway  accident  a 
month  before.  He  was  uninjured  but  badly  fright- 
ened and  the  day  following  the  accident  began  to  drink 
large  amounts  of  water.  As  this,  with  the  excessive 
urination,  continued,  a  physician  was  consulted  and 
sugar  detected  in  the  urine.  The  child  lived  but  four 
months  from  the  time  of  the  fright.  Similar  cases 
where  the  onset  of  the  disease  apparently  dated  from  a 
fright  or  excessive  anxiety  have  come  to  my  attention. 
These  have  usually  been  in  young  individuals. 

Occasionally  pregnancy  seems  to  be  an  etiological 
factor.  In  one  case  of  my  series  there  had  been  a 
pronounced  glycosuria  during  two  pregnancies  which 
had  entirely  subsided  after  the  birth  of  each  child  so 
that  there  was  no  sugar  in  the  urine  and  no  dietetic 
restriction  was  employed.     During  the  third  preg- 

10  Dickinson :  Diabetes,  London,  1875,  p.  75. 


100  DIABETES  MELLITUS 

nancy  there  was  observed  not  only  glycosuria  but  also 
a  moderate  increase  of  thirst  and  following  the  ter- 
mination of  this  pregnancy  the  sugar  excretion  and 
the  symptoms  persisted.  The  woman  became  a  typical 
diabetic.  In  another  case  the  diabetes  developed  dur- 
ing the  first  pregnancy.  Frank11  concluded  that  a 
renal  type  of  diabetes  is  so  common  during  pregnancy 
as  to  be  regarded  as  normal. 

11  Frank :  loc.  cit. 


VIII 
PATHOLOGY 

The  researches  of  Claude  Bernard  formed  the  first 
secure  basis  for  pathological  studies.  These  investiga- 
tions were  directed  in  the  first  instance  to  the  central 
nervous  system  and  the  liver.  Indirectly  much  of  our 
work  at  the  present  time  may  be  traced  to  the  initial 
impetus  of  this  French  physiologist.  Although  the 
most  careful  study  of  the  brain  and  cord  has  failed  to 
reveal  constant  lesions  to  which  may  be  assigned 
etiological  importance  for  diabetes,  the  work  has  not 
been  fruitless.  While  the  number  of  cases  on  record 
are  very  few  wherein  an  injury  or  localized  disease 
process  in  the  brain  or  cord  could  be  demonstrated  as 
a  cause  for  diabetes,  vet  the  relation  of  these  factors 
to  glycosuria  is  well  recognized. 

Traumatism  of  the  head  and  upper  vertebras  is 
frequently  followed  by  transitory  glycosuria.  Jodry  * 
examined  145  cases;  of  these  the  injury  was  to  the 
head  in  50  per  cent. ;  to  the  cord  in  20  per  cent. ;  while 
in  17  per  cent,  the  location  of  the  injury  was  not 
diagnosed.  Of  twenty  cases  of  fracture  of  the  skull 
admitted  to  New  York  Hospital  I  found  sugar  in  the 

1  Jodry:  Lehre  Diabet,  1909. 

101 


102  DIABETES  MELLITUS 

urine  within  the  first  twenty-four  hours  in  fourteen 
(70  per  cent.).  According  to  Lepine  melituria  mani- 
fests itself  in  the  majority  of  these  cases  at  some  time 
during  the  first  week  after  trauma.  It  is  the  con- 
sensus of  opinion  that  a  permanent  diabetes  dating 
from  such  injuries  as  these  described  is  exceedingly 
rare,  although  a  few  cases  are  conceded.  Besides  in- 
juries due  to  external  violence  hemorrhages  in  the 
brain  or  cord  are  occasionally  accompanied  by  sugar 
excretion  and  may  in  hospital  practice  give  rise  to 
diagnostic  embarrassment.  Such  was  the  case  of  a 
young  man  admitted  to  New  York  Hospital.  He 
was  in  coma  on  admission  and  no  history  was  obtain- 
able from  his  friends.  Sugar  was  found  in  the  urine, 
which  appeared  to  point  to  a  diagnosis  of  diabetic 
coma.  At  autopsy  a  small  hemorrhage  was  found  in  the 
medulla,  probably  due  to  a  ruptured  aneurism,  since 
other  aneurismal  dilations  were  noticed  in  the  same 
artery.  It  appears  improbable,  judging  from  the 
good  state  of  this  patient's  nutrition,  that  he  was  a 
diabetic;  and  it  is  certain  that  the  diagnosis  was  not 
properly  grounded.  The  glycosuria  was  secondary  to 
the  injury  of  the  nervous  system. 

Tumors  of  the  central  nervous  system  have  been 
noted  in  association  with  persistent  glycosuria  in  a 
number  of  instances.    To  Levrat  and  Perrotton 2  the 

2  Levrat  and  Perrotton:  These,  Paris,  1853. 


PATHOLOGY  103 

earliest  case  of  this  nature  is  commonly  accredited. 
A  tumor  of  the  choroid  plexus  was  found  in  their  case, 
and  von  Recklinghausen  reported  a  similar  observa- 
tion. Softening,  sclerosis,  hemorrhage,  and  cysticerci 
in  the  neighborhood  of  the  fourth  ventricle  have  been 
observed  in  association  with  glycosuria.3  Likewise 
lesions  in  the  cervical  or  dorsal  cord  have  been  met 
with.  Glycosuria  is  occasionally  found  along  with 
meningitis,  tabes,  and  multiple  sclerosis.4  It  is  diffi- 
cult to  estimate  the  significance  of  these  changes  in 
the  central  nervous  system  in  their  relation  to  a  con- 
stant glycosuria.  That  such  findings  are  exceptional 
is  attested  by  the  analyses  of  Seegen,  who  found  in  the 
autopsy  protocols  of  the  Allgemeine  Krankenhaus 
that  only  nine  per  cent,  of  the  cases  of  diabetes  gave 
evidences  of  pathological  alterations  in  the  nervous 
system.5  In  many  of  these  instances  the  lesions  were 
doubtless  secondary;  moreover  an  analysis  of  four 
hundred  and  eighty-five  cases  of  brain  tumor  by  Bern- 
hardt showed  but  five  with  glycosuria.  Of  these,  two 
were  tumors  of  the  pituitary,  one  each  of  the 
medulla,  cerebellum  and  hemisphere.  And  an  elabo- 
rate summary  of  the  nervous  lesions  found  in  associa- 
tion with  diabetes  made  by  Rosenberger  rather  tends 

"Frerichs:  Uber  Diabetes  Mellitus,  1893. 

4Schultz  and  Knauer:  Alleg.  Zeitschr.  f.  Psychiatrie,  1909,  66,  p.  759. 

5  Seegen:  Der  Diabetes  Mellit,  1893. 


104  DIABETES  MELLITUS 

to  show  that  the  connection  is  casual  in  most  instances.6 
A  striking  fact  which  appears  in  all  the  reports  is 
that  a  glycosuria  is  quite  as  apt  to  result  from  a  lesion 
remote  from  the  "  diabetic  centre  "  as  from  one  near 
to  it.  The  explanation  offered  that  lesions  are  not 
irritative  can  be  accepted  only  with  considerable 
reserve. 

The  association  with  tumors  in  or  near  the  hy- 
pophysis, however,  suggests  much  more  cleanly  a 
causal  relation.  The  complication  of  acromegaly  with 
diabetes  has  been  given  considerable  attention  and 
many  observations  are  available.  A  frank  glycosuria 
or  lowering  of  the  assimilation  limit  as  evidenced  by 
an  alimentary  sugar  excretion  has  been  observed  in  a 
large  percentage  of  the  cases.  Of  176  cases  collected 
by  Borchardt 7  there  was  diabetes  present  in  63  and 
alimentary  glucosuria  in  eight,  viz.,  40  per  cent, 
showed  weakness  of  the  carbohydrate  metabolism. 
Cushing  and  his  pupils  have  shown  that  the  pituitary 
gland  is  important  in  regulating  sugar  metabolism.8 
This  function  is  more  intimately  related  to  the  pos- 
terior lobe  of  the  hypophysis,  the  removal  of  which  in 
dogs  increases  markedly  the  tolerance  for  carbohy- 
drates and  the  intravenous  administration  of  extracts 
of  this  lobe  causes  glycosuria.     From  the  evidence 

6  Rosenberger :  Die  Ursachen  der  Glycosuria,  Miinchen,  1911,  p.  287. 

7  Zeitschr.  f.  klin.  Med.,  1908,  66,  p.  332. 

8  Cushing:  The  Pituitary  Body  and  its  Disorders,  1912,  pp.  17,  261. 


PATHOLOGY  105 

thus  far  obtainable  it  is  to  be  inferred  that  glycosuria 
might  be  expected  to  result  from  tumors  of  the  hypo- 
physeal region  where  the  posterior  lobe  or  the  stalk  of 
the  pituitary  is  involved,  either  directly  or  by  pressure. 
On  the  other  hand,  processes  resulting  in  diminished 
activity  of  this  lobe  are  associated  with  increased 
tolerance  for  glucose.  By  no  means  are  all  cases  of 
acromegaly  accompanied  by  melituria ; 9  whether  there 
be  as  a  rule  diminished  tolerance  it  is  not  possible  to 
state,10  since  many  reported  cases  of  this  disease  have 
not  been  studied  from  this  point  of  view.  In  one 
case  of  acromegaly  which  I  was  able  to  study  over  a 
long  period  of  time  there  was  no  diminution  in  the 
tolerance,  although  at  autopsy  marked  hyaline  degen- 
eration of  many  islands  of  Langerhans  was  noted. 
There  was  also  hypertrophy  of  intact  islands  which, 
possibly,  is  the  explanation  for  the  absence  of  diabetes. 
The  early  importance  assigned  to  the  liver  as  a 
storehouse  for  glycogen  caused  this  organ  to  be 
studied  with  particular  care  in  cases  of  diabetes 
mellitus.  A  case  of  cirrhosis  of  the  liver  and  dia- 
betes in  an  alcoholic  subject  interested  Bernard  be- 
cause as  the  cirrhosis  progressed  there  was  a  diminu- 
tion of  the  sugar  excretion  to  mere  traces.  Bernard 
interpreted  these  facts  as  indicative  of  excitation  of 

'Claude:  Compt.  Rend.,  1911,  71,  p.  75. 

10Rotky:  Zentralblatt  f.  Physiol,  u.  Path.  d.  Stoff.,  1911,  p.  173. 

8 


106  DIABETES  MELLITUS 

the  glycogenolytic  function  by  the  disease  process 
which  later  totally  destroyed  this  function  as  marked 
by  the  disappearance  of  sugar  from  the  urine,  a  view 
that  has  only  an  historical  interest.  The  association 
of  cirrhosis  with  diabetes  is  not,  however,  very 
common.  Naunyn  noted  twenty-nine  instances 
among  two  hundred  and  eighty-six  cases  of  diabetes 
(ten  per  cent.),  not  a  large  proportion.  That  the 
diabetes  is  not  dependent  upon  the  cirrhosis  is  sup- 
ported by  Frerichs'  observation  of  cases  of  cirrhosis 
with  extreme  degeneration  changes  without  any  evi- 
dence of  diabetes  during  life.  The  frequency  of 
association  of  degenerative  changes  in  the  liver  and 
pancreas,  however,  has  been  remarked  by  many  pathol- 
ogists. From  a  detailed  study  of  the  lesions  in  the 
pancreas  accompanying  various  types  of  cirrhosis 
Lafas  arrived  at  the  conclusion  that  the  changes  in 
both  organs  are  a  result  of  the  same  etiological  factors, 
and  that  the  pancreatic  changes  are  not  dependent 
upon  those  in  the  liver.11  Hirschfeld  appears  to 
concur  in  this  opinion  and  adds  that  the  noxious  agent, 
whatever  it  may  be,  is  very  seldom  transported  to  the 
liver  by  way  of  the  portal  vein  but  when  so  conveyed 
the  liver  alone  suffers.  When,  however,  the  agent  is 
conveyed  by  the  arterial  circulation  both  pancreas  and 
liver  are  affected.     An  illustration  of  this  state  of 

"Lafas:  Arch.  gen.  d.  Med.,  1900,  in,  539. 


PATHOLOGY  107 

affairs  where  both  liver  and  pancreas  are  simultane- 
ously damaged  by  a  single  agent  is  found  in  the  con- 
dition described  by  von  Recklinghausen  as  hemochro- 
matosis. In  this  disorder  there  is  found  along  with 
degenerative  processes  in  the  cells  of  the  gastroin- 
testinal tract,  heart  and  kidneys,  a  general  deposi- 
tion of  pigment  throughout  the  tissues,  cirrhosis  of 
the  liver  (cirrhose  pigmentaire ) ,  and  chronic  inter- 
stitial pancreatitis.  Probably  a  more  complete  de- 
velopment of  this  disorder  was  described  by  Hanot 
and  Chauffard12  as  Bronzed  Diabetes;  the  patho- 
logical lesions  are  the  same  as  in  hemochromatosis 
only  that  the  pigmentation  is  more  intense.  Opie  be- 
lieves hemochromatosis  to  be  a  clinical  entity  and  that 
the  diabetes  becomes  manifest  in  consequence  of  ad- 
vanced pancreatic  degeneration.  The  pancreatic 
lesion  in  this  disease  is  of  the  interacinar  type  of 
chronic  inflammation  and  implicates  the  islands  of  Lan- 
gerhans,  in  consequence  of  which  glycosuria  ensues. 

The  opinion  of  Rossle  that  diabetes  may  be  diag- 
nosed at  autopsy  with  more  certainty  from  the  hepatic 
changes  than  from  the  pancreas  has  not  met  with  con- 
firmation.13 In  addition  to  an  increase  in  the  weight 
of  the  liver  which  Saundby  remarked,  Rossle  called 
attention    specially    to    a    fatty    degeneration    of 

12  Hanot  and  Chauffard:  Rev.  de  med.,  1832,  h,  p.  385. 
"Rossle:  Verhn.  deutsch.  path.  Gesellsch.,  1907. 


108  DIABETES  MELLITUS 

Kupffer's  stellar  cells  and  certain  refractile  bands 
along  the  capillaries  which  are  said  to  be  characteristic. 
The  liver  in  diabetes  is  often  large  and  fatty  but 
consensus  of  opinion,  however,  is  that  there  are  no 
constant  or  characteristic  changes  in  this  disease. 

PANCREAS 

The  association  of  pathological  changes  in  the 
pancreas  with  glycosuria  seems  to  have  been  first  sug- 
gested by  Cowley  ( 1788) .  He  recorded  as  the  signifi- 
cant fact  disclosed  by  an  autopsy  on  one  of  his  cases 
of  diabetes  an  atrophy  of  the  pancreas  and  many 
calculi  within  the  ducts.  Chop  art  made  a  similar 
observation  at  a  later  date,  and  Bright  reported  an  in- 
stance of  diabetes  in  association  with  tumor  of  the  pan- 
creas. It  does  not  appear  that  anyone  regarded  affec- 
tions of  this  gland  as  responsible  for  the  glycosuria 
until  Bouchardat  did  so  in  1846.14  It  was,  however, 
to  a  perversion  in  the  digestive  function  of  the  pan- 
creas that  Bouchardat  assigned  the  diabetes.  A 
quarter  of  a  century  later  Lancereaux  definitely  at- 
tributed to  pancreatic  disease  a  type  of  diabetes  re- 
markable for  its  severity  and  named  by  him  "  diabete 
maigre."  More  complete  knowledge  has  disclosed  the 
inadequacy  of  this  division.  The  pancreatic  theory  of 
diabetes  was  finally  established  by  the  experimental 

14  Traite  du  Diabete,  1875. 


PATHOLOGY  109 

work  of  von  Mering  and  Minkowski,  and  these  ex- 
periments stimulated  a  renewed  interest  among  pathol- 
ogists in  determining  the  nature  and  significance  of 
the  lesions  noted  at  autopsies  done  on  cases  of  dia- 
betes. Since  the  earlier  studies  in  this  field  were  made 
for  the  most  part  without  the  aid  of  the  microscope  it 
is  as  one  might  expect,  that  the  frequency  and  char- 
acter of  morbid  states  found  in  the  pancreas  varied 
considerably  according  to  different  students.  Judg- 
ing from  the  macroscopic  appearance  of  the  pancreas 
a  chronic  sclerosis  was  the  condition  most  commonly 
observed  and  this  was  found  in  from  nineteen  to 
thirty-six  per  cent,  of  the  cases  of  diabetes  examined. 
With  the  aid  of  the  microscope  many  conditions  were 
disclosed  which  had  hitherto  escaped  detection  and  the 
frequency  with  which  lesions  were  observed  rose  con- 
siderably (Williamson,  79  per  cent.).  The  nature 
and  frequency  of  the  various  lesions  is  shown  in  the 
following  table  compiled  by  Hansemann,15  of  fifty- 
four  cases  which  he  studied  in  the  Pathological  Insti- 
tute in  Berlin: 

Atrophy   (granular)    36 

Fibrous  induration    3 

Complicated  case   1 

Normal  pancreas   8 

Pancreas  not  noted 6 

Total 54 

*  Zeitschr.  f.  klin.  Med.,  1894,  26,  p.  191. 


110  DIABETES  MELLITUS 

In  his  last  communication  on  the  subject  Hansemann 
asserted  that  changes  in  the  pancreas  are  demonstra- 
ble in  every  case  of  true  diabetes  provided  the  gland  be 
examined  before  autodigestion  takes  place.  What  the 
various  lesions  are  that  interest  pathologists  to-day  we 
must  consider  somewhat  minutely. 

Doubtless  influenced  by  a  suggestion  of  Laguesse 
that  the  islands  of  Langerhans  may  be  related  to  the 
internal  secretion  of  the  pancreas,  Schafer  16  advanced 
the  hypothesis  in  1895  that  pathological  alterations  of 
these  structures  are  responsible  for  diabetes.  Some 
slight  confirmatory  evidence  to  the  theory  was  af- 
forded by  studies  of  Ssobolew  in  1900,  but  to  Opie  is 
due  the  chief  credit  for  what  we  know  of  these  changes. 
Opie  observed  sclerosis  or  hyaline  degeneration  of  the 
islands  as  the  most  striking  lesions.  These  lesions 
vary  in  degree ;  in  some  cases  studied  no  islands  were 
left  intact.  Hyaline  change  may  or  may  not  be  ac- 
companied by  connective  tissue  proliferation  about 
the  islands.  The  frequency  of  these  lesions  as  noted 
by  various  competent  pathologists  appears  in  the  fol- 
lowing statistics  collected  by  Opie.17 

Pancreatic  Lesions: 

Interacinar  pancreatitis  (fine  sclerosis)    125     (43.4%) 

Interlobular  pancreatitis  (coarse  sclerosis)   13 

Lipomatosis 18 

"Schafer:  Lancet,  1895,  n,  p.  321. 
"Diseases  of  Pancreas;  1910,  p.  321. 


PATHOLOGY  111 

Calculi    9 

Cyst    1 

Carcinoma 5 

Focal  necrosis    2 

Atrophy    65     (22.5%) 

Lesions  of  the  Islands  of  Langerhans  with  Normal  Parenchyma: 

Hyaline   degeneration    6    \ 

Sclerosis  2    (.   3.8  % 

Adenoma-like  hypertrophy  3     i 

No  Lesions  of  Pancreas: 

Pancreas  normal   34    \ 

Pancreas  normal;  number  of  islands  of  Langer-  C    13.5  % 

hans    diminished    5     1 

Total 288 

A  more  satisfactory  estimate  is  perhaps  adduced 
from  the  results  of  a  single  observer  studying  a  large 
number  of  cases  as  the  following  table  from  Cecil 
indicates : 

1.  Chronic  Inflammation  of  the  Pancreas: 

Interacinar  pancreatitis;  sclerosis  of  islands  of  Langer- 
hans      39 

Interlobular  pancreatitis;  sclerosis  of  islands  of  Lan- 
gerhans         4 

Interacinar  pancreatitis;  hyaline  degeneration  of  islands 
of  Langerhans   19 

Interacinar  pancreatitis  with  lipomatosis;  sclerosis  of 
islands  of  Langerhans 2 

Interacinar  pancreatitis  with  lipomatosis;  hyaline  de- 
generation of  islands  of  Langerhans   1 

Interacinar  pancreatitis  with  hemochromatosis 2 

2.  Parenchyma  Normal: 

Lesions  of  Islands  of  Langerhans. 

Sclerosis  of  islands 4 

Hyaline  degeneration    7 

Infiltration  of  leucocytes  about  islands 1 

3.  Pancreas  Normal 11 


112  DIABETES  MELLITUS 

Reducing,  then,  these  figures  to  percentages,  Cecil 
found  88  per  cent,  of  his  cases  showed  definite  changes 
in  the  islands;  these  lesions  were  a  hyaline  degenera- 
tion in  30  per  cent,  and  a  sclerosis  in  54  per  cent. 
Sclerosis  of  the  islands  is  usually  associated  with 
chronic  interacinar  pancreatitis.  The  pancreas  was 
normal  in  12  per  cent,  of  the  series.  Of  these  cases 
classed  as  normal  the  gland  was  small  in  some  in- 
stances and  there  appeared  to  be  a  diminution  in  the 
number  of  islands.  It  is  a  remarkable  fact  that  of  the 
eleven  cases  studied  by  Cecil  where  the  pancreas  is 
normal  nine  may  be  classed  as  young  individuals ;  the 
oldest  thirty- two;  the  youngest  nine  years  of  age,  and 
in  all  the  diabetes  ran  a  rapid  course. 

As  to  the  various  lesions  noted  by  pathologists  the 
question  arises  is  any  one  of  them  related  as  a  causal 
agent  to  diabetes  and  if  so  which  one?  Chronic  pan- 
creatitis is  not  so  uncommon  as  formerly  thought  and 
by  no  means  always  attended  by  glycosuria;  neither 
does  an  extensive  destruction  of  the  parenchyma  of 
the  gland  as  a  rule  cause  diabetes  since  with  cancer  of 
the  pancreas  diabetes  is  exceptional.  Sauerbeck 
found  carcinoma  five  times  in  his  series  of  288  cases 
of  diabetes.  Acute  processes  in  the  pancreas  attended 
with  necrosis  may  bring  about  extreme  destruction  of 
the  gland  parenchyma,  yet  Egdahl  found  glycosuria 


PATHOLOGY  113 

with  only  six  out  of  one  hundred  and  five  such  cases.18 
Since  the  appearance  of  sugar  in  the  urine  is  not 
the  usual  sequence  of  all  forms  of  chronic  pancreatitis 
nor  of  those  morbid  processes  which  entail  consider- 
able loss  of  the  gland  substance,  it  must  follow  that  if 
a  lesion  in  the  pancreas  is  responsible  for  glycosuria 
this  lesion  must  be  in  some  element  of  the  gland  that 
often  escapes  injury  in  the  more  general  inflamma- 
tions. A  case  which  may  be  significant  is  reported  by 
Scott 10  in  which  the  islands  of  Langerhans  were  the 
only  recognizable  remains  of  the  gland  in  a  case  of 
malignant  disease  of  the  pancreas.  There  was  no  sugar 
in  the  urine.  Opie  argues  that  extensive  degenera- 
tive changes  may  affect  the  parenchyma  and  leave  the 
islands  of  Langerhans  intact.  On  the  other  hand,  the 
islands  are  often  subject  to  hyaline  degeneration 
where  in  all  respects  the  pancreas  is  practically  nor- 
mal and  in  such  instances  there  is  a  history  during 
life  of  diabetes.  Interlobular  pancreatitis  does  not 
usually  implicate  the  islands  until  the  process  is  quite 
advanced.  With  these  cases  diabetes  is  exceptional. 
In  support  of  Opie's  theory  is  the  statement  of  Sauer- 
beck that  he  has  been  able  to  find  no  cases  of  severe 
lesions  of  the  islands  of  Langerhans  that  were  not 
accompanied  by  diabetes.     The  positive  evidence  of 

18  Bull.  Johns  Hopkins  Hospital,  1906,  xvii,  p.  <2Q5. 

19  Scott:  Jour.  Path,  and  Bact.,  1907,  xi,  p.  458. 


114  DIABETES  MELLITUS 

Weichselbaum  is  based  upon  the  microscopic  examina- 
tion of  the  pancreas  of  one  hundred  and  eighty-three 
cases  of  diabetes;  in  all  lesions  were  found  in  the 
islands  of  Langerhans.  These  lesions  are  of  three 
types :  hydropic  degeneration  (most  common  in  young 
individuals),  sclerotic  and  atrophic  islands,  and,  fi- 
nally, hyaline  degeneration.20 

The  so-called  insular  hypothesis  has  been  con- 
sidered first  because  it  is  doubtless  the  dominant  theory 
at  the  present  time.  The  older  acinar  hypothesis  has, 
however,  able  advocates.  Hansemann21  claimed  in 
1894  to  distinguish  in  a  "granular  atrophy"  the  char- 
acteristic lesion  of  diabetes.  Opie  designates  the  same 
change  as  an  interacinar  fibrosis.  Hansemann  places 
special  stress  upon  changes  in  the  acini,  and  in  his 
later  papers  22  he  has  supported  Herxheimer  in  con- 
tending that  the  islets  are  not  independent  structures 
but  are  constantly  formed  from  acini  and  that  these 
structures  bear  no  relation  to  diabetes.  This  doctrine 
is  also  advocated  by  Karakascheff  of  Marchand's 
laboratory.     Though  not  subscribing  to  the  idea  of 

"Ina  case  of  acromegaly  that  I  examined  many  of  the  islands  of 
Langerhans  showed  a  marked  degree  of  hyaline  degeneration.  There 
were  also  to  be  found  occasional  islands  that  appeared  normal  and  were 
hypertrophied.  There  was  in  this  case  no  glucosuria.  It  is  conceivable 
that  the  few  intact  islands  by  hypertrophy  were  adequate  to  the  demands. 
Ohlmacher  has  mentioned  a  similar  case. 

"  Zeit.  f.  klin.  Med.,  1894,  26,  p.  191. 

22  Berlin,  klin.  Wochenschr.,  1912,  49,  p.  927. 


PATHOLOGY  115 

transitions  of  acini  into  islets,  Lomboroso  has  given 
his  support  to  the  theory  that  some  disorder  of  the 
pancreas  as  a  whole  is  accountable  for  diabetes.23 

These  in  brief  outline  are  the  theories  held  by  the 
pathologists  at  present.  An  impartial  observer  must 
be  struck  in  reviewing  the  evidence  presented  with 
the  large  place  held  by  the  personal  equation.  It 
seems  doubtful  if  agreement  could  be  made  as  to  the 
nature  of  a  specific  lesion  and  equally  doubtful  in 
many  cases  if  diagnosis  of  diabetes  could  be  estab- 
lished with  facility  by  examination  of  the  pancreas 
without  knowledge  of  the  clinical  history.  From  the 
experimental  side  some  evidence  has  been  secured  in 
support  of  the  theory  that  the  lesions  of  the  islands 
of  Langerhans  are  accountable  for  diabetes.  By 
ligating  the  pancreatic  ducts  of  a  dog  MacCallum  24 
produced  an  extreme  grade  of  degeneration  so  that 
after  a  year  only  a  vestige  of  pancreas  remained. 
This  remnant  of  pancreas  was  composed  practically 
entirely  of  islands.  The  atrophy  of  the  gland  was  not 
accompanied  by  glycosuria,  but  when  this  remnant 
of  pancreas  was  finally  removed  the  dog  developed  at 
once  an  intense  and  persistent  glycosuria.  Other  ex- 
perimenters 25  have  ligated  the  pancreatic  ducts  in 

28  Ergeb.  der  Physiol.,  1910,  9,  1. 

M MacCallum:  Johns  Hopkins  Hospital  Bull.,  1909,  20,  p.  255. 

*  Pratt:  Arch,  of  Intern.  Med.,  1911,  7,  pp.  665-679. 


116  DIABETES  MELLITUS 

various  animals  with  results  that  are  not  in  entire 
accord.  By  some  it  is  claimed  with  MacCallum  that 
only  islands  remain  in  non-diabetic  animals.  Others 
find  acini  as  well  as  islets.  So  the  validity  of  the 
island  doctrine  cannot  be  held  established  by  these  ex- 
periments. That  the  pancreas  undergoes  marked 
atrophy  after  ligation  of  the  ducts  is  admitted  but  the 
finding  of  islets  only  in  this  atrophied  remnant  does 
not  overthrow  Herxheimer's  assertion  that  these  islets 
simply  present  the  last  and  most  resistant  state  of 
acinar  transformation.  The  experiments  of  Allen  26 
are  more  to  the  point.  He  found  in  a  large  number  of 
animals  that  after  duct  ligation  the  acinar  tissue 
might  be  well  preserved  and  yet  diabetes  develop. 
"The  contrast  between  the  two  series  (non-diabetic  and 
diabetic)  seems  to  be  found  in  just  one  point;  in  the 
former  series,  preservation  of  the  islets ;  in  the  latter, 
degeneration  of  the  islets."  While  evidence  at  present 
is  mostly  favorable  to  the  island  hypothesis  the  ques- 
tion must  be  left  open  as  demonstration  is  lacking. 

Finally  with  regard  to  these  cases  of  diabetes 
where  no  lesions  are  demonstrable  in  the  pancreas,  it 
is  conceivable  as  Opie  has  suggested  that  simply  a 
diminution  in  the  number  of  islands  (congenital)  may 
give  rise  to  diabetes.    This  seems  possible.    It  is  also 

'"Allen:  Glycosuria,  Boston,  1913,  p.  980. 


PATHOLOGY  117 

probable  that  we  shall  recognize  in  the  future  several 
types  of  diabetes,  at  present  not  differentiated,  en- 
tirely independent  of  pancreatic  disease ;  such  as  that 
exemplified  in  disease  of  the  hypophysis. 

In  considering  the  anatomical  findings  in  the  heart 
and  kidneys  due  regard  has  not  usually  been  taken  of 
the  age  of  the  patient.  The  pathological  lesions  that 
have  been  most  often  noted  in  those  tissues  are  found 
almost  exclusively  in  the  older  individuals. 

The  lesions  of  the  heart  in  diabetes  are  changes  in 
the  myocardium.  In  cases  with  advanced  sclerosis  of 
the  arteries  it  occasionally  happens  that  the  valve 
cusps  may  be  involved  in  the  process  and  thereby  pro- 
duce incompetence,  but  this  is  not  of  peculiar  sig- 
nificance. Also  fibrinous  pericarditis  or  adherent 
pericardium  is  sometimes  observed  in  cases  of  long 
standing,  usually  in  association  with  sclerotic  kidneys. 
Older  writers  make  reference  to  an  hypertrophy  of  the 
heart  occurring  along  with  renal  hypertrophy.  This  is 
probably  to  be  regarded  as  secondary  to  renal  disease 
also.  The  degenerations  of  the  myocardium  are  chiefly 
of  the  fatty  type  and  are  found  in  over  three-quarters 
of  the  cases  where  any  lesion  is  notable.  Exceptionally 
there  is  brown  atrophy.  The  glycogenic  degeneration 
described  by  Frerichs  is  analogous  to  that  observed  in 
the  kidney.  In  young  patients  and  in  children  I  have 
observed  no  change  in  the  myocardium  other  than  a 


118  DIABETES  MELLITUS 

slight  cloudy  swelling  of  the  cells  in  cases  that  have 
died  in  coma. 

The  kidneys  in  these  young  subjects  have  been 
quite  normal  except  for  a  moderate  degree  of  fatty 
change  in  the  cells — a  picture  very  common  in  all 
emaciating  diseases.  In  the  older  subjects  of  dia- 
betes a  normal  kidney  is  exceptional,  at  least  in  my 
experience.  Seegen  noted  parenchymatous  nephritis 
as  the  most  common  lesion  in  his  series  of  cases  at 
the  Vienna  Pathological  Institute,  contracted  kidney 
forming  less  than  one  per  cent.  Since  arteriosclerosis 
is  so  commonly  an  accompanying  disorder  with  dia- 
betes it  is  not  remarkable  that  the  kidneys  are  fre- 
quently diseased.  The  type  of  lesion  is  that  form  of 
diffuse  nephritis  which  is  commonly  spoken  of  in 
America  as  the  arteriosclerotic  kidney.  There  is  not, 
however,  much  reduction  in  the  total  renal  substance 
and  the  glomerular  tufts  are  more  apt  to  present 
hyaline  changes  than  complete  fibrosis. 

Frerichs  and  Ehrlich  have  described  as  charac- 
teristic of  the  kidney  in  diabetes  a  form  of  glycogenic 
degeneration.  This  observation  lacks  confirmation  in 
recent  literature  though  the  lesion  is  familiar  to  pathol- 
ogists since  it  is  noted  in  the  liver  and  some  tumors. 

There  have  been  no  studies  made  of  the  kidneys  in 
"renal  diabetes"  that  offer  an  explanation  of  this 
disorder. 


PATHOLOGY  119 

BLOOD  IN  DIABETES  MELLITUS 

The  water  content  of  the  blood  in  diabetes  is  sub- 
ject to  considerable  variation.  The  normal  percentage 
of  water  in  blood  is  about  78,  and  in  diabetes  there 
appears  a  slight  tendency  toward  concentration;  with 
some  cases  of  coma  there  has  been  noted  as  low  as  73 
per  cent,  of  water  and  to  this  fact  Rumpf 27  has 
assigned  special  significance  in  explaining  the  coma. 
This  observation  has  not  been  substantiated  by  further 
investigation  and  the  fact  is  explicable  in  the  coma 
state  by  the  loss  through  the  lungs  and  urine  of  fluid 
which  is  not  replenished  by  the  usual  ingest.  That 
concentration  of  the  blood  is  unusual  is  evidenced  by 
the  freezing  point  which  is  usually  within  normal 
limits.  The  variations  have  been  studied  by  refrac- 
tion methods  with  like  results.28  Unless  there  are 
complications  to  the  diabetes  the  number  of  erythro- 
cytes and  leucocytes  is  normal.  In  advanced  cases 
with  marked  loss  in  weight  an  anaemia  of  the  secondary 
type  may  be  noted,  but  it  is  often  remarkable  that  the 
haemoglobin  is  found  but  little  diminished  with  very 
severe  cases.  The  two  most  characteristic  alterations 
of  the  blood  in  diabetes  are  the  increase  in  its  content 

"Rumpf:  Zeit.  f.  klin.  Med.,  1902,  45,  p.  260. 

28  Ref raktometrische  Blutuntersuchung.     Reiss.  Ergeb.  f.  inn.  Med. 
u.  Kinderheilk.,  1913,  x,  p.  595. 


120  DIABETES  MELLITUS 

of  sugar  and  of  lipoids.  An  hyperglycemia  is  found 
at  some  period  with  all  diabetics.  The  amount  of 
glucose  recoverable  from  normal  blood  depends  to 
some  extent  upon  the  method  of  analysis  employed  and 
varies  between  .06  and  .12  per  cent.  Under  conditions 
of  disease  these  amounts  may  be  increased  several 
fold.  With  severe  diabetes  it  is  not  unusual  to  find 
values  of  0.3  per  cent,  or  over ;  and  Weiland  noted  .79 
per  cent,  and  .95  per  cent,  in  coma  cases.  Excep- 
tionally very  high  figures  for  .blood  sugar  are  also 
observed  in  uremic  coma;  in  one  of  my  cases  .51  per 
cent.,  though  there  had  been  no  sugar  in  the  urine  dur- 
ing the  period  prior  to  coma  nor  was  there  anything 
in  the  history  that  suggested  diabetes.  A  moderate 
increase  in  the  blood  sugar  without  glycosuria  is  ob- 
served in  fevers  and  with  exophthalmic  goitre.  The 
degree  of  hyperglycemia  with  diabetic  patients  de- 
pends on  several  factors.  First  among  these  is  the 
severity  of  the  disease.  In  young  patients  where  the 
course  of  the  malady  is  rapid  the  blood  sugar  is  much 
higher  than  with  elderly  patients  in  whom  the  disease 
may  occasion  few  or  no  symptoms.  It  may  often  be 
observed  again,  that  in  the  earlier  stages  there  is  but 
slight  hyperglycemia  but  later  as  the  tolerance  dimin- 
ishes the  increase  in  blood  sugar  is  twice  or  thrice  nor- 
mal. A  man  of  51  years  sought  advice  in  June,  1912, 
for  what  appeared  to  be  a  mild  type  of  diabetes.    It 


PATHOLOGY  121 

was  found  by  tests  that  he  could  utilize  80  grammes 
of  starch.  His  blood  sugar,  before  treatment  was 
begun,  was  .17  per  cent.  During  the  next  nine  months 
the  urine  remained  free  of  sugar  with  a  carbohydrate 
tolerance  of  70  to  80  grammes.  In  1913  following  a 
period  of  hard  mental  work,  sugar  appeared  in  the 
urine  in  considerable  amounts  and  investigation  re- 
vealed that  he  could  not  utilize  more  than  ten  grammes 
of  ingested  starch.  The  blood  sugar  had  increased  to 
.29  per  cent. 

When  treatment  is  met  with  success  and  the  urine 
can  be  kept  glucose-free  for  a  period  there  is  a  gradual 
fall  in  the  glucose  of  the  blood  to  nearly  or  quite  nor- 
mal amounts.  This  response  in  the  blood  is  not  im- 
mediate however.  With  many  cases  it  is  found  that 
notwithstanding  the  fact  that  there  has  been  no  sugar 
excretion  for  a  couple  of  weeks  or  more,  yet  the  values 
for  blood  sugar  are  .05  to  .08  per  cent,  above  normal. 
Just  what  explanation  is  to  be  given  for  the  absence  of 
glycosuria  under  these  circumstances  is  not  entirely 
clear.  It  has  been  assumed  that  a  lessened  permea- 
bility of  the  kidneys  exists  and  with  many  cases  there 
may  be  ground  for  suspecting  nephritis.  But  it  might 
appear  that  an  adequate  explanation  would  also 
clarify  the  absence  of  glycosuria  with  non-diabetic 
hyperglycemia.  The  reasons  may  lie  in  the  state  of 
the  blood  sugar,  as  some,  notably  Lepine,  believe. 


122  DIABETES  MELLITUS 

The  doctrine  of  a  colloidal  suspension  of  blood  sugar 
has  been  discussed  in  another  chapter. 

A  much  more  variable  condition  than  the  hyper- 
glycemia is  a  lipasmia.  Normally  the  blood  content 
in  lipoid  substances  is  about  one  per  cent.  An  in- 
crease beyond  the  normal  bounds  is  found  not  only  in 
some  cases  of  diabetes  but  also  in  severe  anaemias, 
eclampsia,  cholasmia,  and  occasionally  in  some  other 
diseases.  The  highest  percentages  for  blood  fats  have 
been  observed  in  severe  cases  of  acidosis;  indeed,  it 
appears  to  be  intimately  related  to  this  condition, 
since  in  cases  under  close  observation  the  lipasmia  has 
disappeared  with  improvement  and  reappeared  with 
exacerbations  of  the  acid  intoxication.  Lipsemia  is, 
however,  by  no  means  an  invariable  manifestation  in 
severe  acidosis,  nor  even  in  coma.  When  evident  it  is 
most  pronounced  in  coma.  Stadelmann  found  15  per 
cent,  of  lipoid  substances  in  one  case;  it  is  very  ex- 
ceptional though  to  find  more  than  4  or  5  per  cent.29 
This  increase  is  only  in  part  due  to  neutral  fat  (tri- 
glycerides) since  both  cholesterin  and  lecithin  are 
above  normal,  and  the  former  may  at  times  constitute 
30  or  more  per  cent,  of  the  total  lipoid  of  blood.  The 
significance  of  this  enormous  increase  in  the  fatty  sub- 
stances is  not  known.    That  it  is  not  a  consequence  of 

29  Fischer:  Ueber  Lipamie  u.  Cholesteramie.  Virchow's  Arch.,  1903, 
172,  p.  30. 


PATHOLOGY  123 

the  fat-containing  diet  has  been  shown,30  and  it  seems 
equally  doubtful  if  the  cholesterin  is  to  be  regarded  as  a 
product  of  broken-down  cellular  tissue — a  theory  first 
advanced  by  Flint  and  recently  revived.  The  impor- 
tance of  lecithin  and  like  substances  in  serology  has 
awakened  a  renewed  interest  in  the  whole  subject 31 
and  it  may  be  expected  that  the  problem  of  lipsemia 
will  be  solved  in  the  not  remote  future. 

30  Klemperer  and  Umber:  Zeit.  f.  klin.  Med.,  1908,  65,  p.  340. 

31  Burger  and  Beumer:  Berlin,  klin.  Wochenschr.,  1913,  50,  p.  112. 


IX 

SYMPTOMATOLOGY 

The  classic  symptoms  of  diabetes,  thirst,  wasting, 
and  increased  urine  volume,  are  mentioned  in  the 
oldest  literature  of  the  disease.  These  symptoms  are 
not  always  present  in  a  marked  degree.  Many  dia- 
betics who  have  passed  the  meridian  of  life  do  not  lose 
weight  and  the  urine  excretion  is  hardly  above  normal. 
This  difference,  in  connection  with  others  to  be  men- 
tioned, led  clinicians  to  differentiate  between  the 
severest  forms  of  the  disorder  and  those  where  the 
course  is  less  rapid.  Formerly  these  types  were  desig- 
nated as  acute  and  chronic,  now  more  generally  by 
the  descriptive  terms  severe  and  mild. 

The  mildest  types  of  diabetes  can  undoubtedly 
exist  for  some  period  without  producing  symptoms. 
Several  men  have  consulted  me  who  first  became 
aware  of  their  condition  on  being  rejected  by  insur- 
ance companies.  These  cases  probably  represent  a 
very  early  period  in  the  disease.  They  are  usually  in 
the  fifth  or  sixth  decade  of  life  although  one  case  was 
under  thirty.  Absence  of  symptoms  is  unusual;  but 
with  hospital  patients  the  indications  of  disease  are 

124 


SYMPTOMATOLOGY  125 

frequently  not  observed.  Here  carbuncles,  boils,  pru- 
ritus, or  gangrene  of  a  toe  is  often  the  occasion  for 
coming  to  the  clinic.  With  more  sensitive  and  intro- 
spective persons  an  increase  in  frequency  of  urination 
is  sufficient  annoyance  to  require  investigation.  Some 
cases  are  detected  by  the  ophthalmologists  in  associa- 
tion with  cataract.  These  examples  serve  only  to  show 
the  bland  form  that  the  disease  may  at  times  assume 
and  the  variety  of  symptoms  connected  with  it. 

As  a  rule  there  is  not  only  distressing  thirst  and 
polyuria  but  the  history  of  some  loss  in  weight.  In 
severe  forms,  especially  in  children,  the  loss  of  flesh  is 
rapid  in  the  extreme,  rivalling  in  this  respect  the 
febrile  diseases.  With  these  cases  the  amount  of  urine 
is  sometimes  enormous,  ten  or  even  fifteen  litres  per 
day.  The  rapid  wasting  is  readily  explained  by  the  loss 
in  sugar  through  the  urine.  One  of  my  cases,  a  young 
woman,  voided  daily  an  average  of  eight  litres  of  urine 
containing  from  500  to  600  grammes  of  sugar ;  a  loss 
to  the  body  of  from  2000  to  2500  calories.  This  loss  of 
sugar  accounts  not  only  for  the  emaciation  but  also  for 
the  weakness  and  the  voracious  appetite.  It  is,  under 
such  conditions,  almost  impossible  to  consume  suf- 
ficient food  to  keep  pace  with  the  disease  unless  the 
diet  be  arranged  to  meet  special  demands. 

Many  diabetics  have  a  type  of  f  acies  that  is  char- 
acteristic; so  much  so  that  some  students  of  the  dis- 
• 


126  DIABETES  MELLITUS 

ease  have  believed  a  diagnosis  possible  on  inspection. 
The  characteristic  element  is  the  patient's  color.  This 
may  be  so  brilliant  as  to  suggest  blooming  health. 
Closer  attention,  however,  reveals  a  difference  from 
normal  in  that  the  ruddy  tint  is  deeper  than  normal 
pink,  approaching  the  red  of  sunburn,  and  spreads 
from  high  on  the  cheek,  fading  only  on  the  neck.  This 
diabetic  complexion,  if  it  may  be  so  styled,  is  usually 
noted  with  young  patients  and  then  there  are  often  evi- 
dent the  lines  about  the  mouth  which  one  associates 
with  rapid  loss  of  weight.  Aside  from  the  polydipsia, 
polyuria,  and  wasting,  there  are  few  symptoms  usually 
noted  in  the  early  stage  of  the  disease;  the  majority 
may  quite  correctly  be  regarded  as  complications  or 
sequelae.  An  abnormal  appetite  accompanies  the 
severe  types  of  the  disease  and  is  a  direct  consequence 
of  the  enormous  sugar  loss  through  the  urine.  Many 
patients  complain  of  an  unpleasant  taste  in  the  mouth. 
Dr.  Camplin,  a  friend  of  Bright,  himself  a  diabetic, 
described  this  taste  as  "sweetish  and  cloying."  It  has 
been  repeatedly  likened  to  the  taste  imparted  by  a 
coin  in  the  mouth.  Not  infrequently  there  are  cramps 
in  the  legs,  particularly  in  the  calves;  coming  on  at 
any  time,  but  especially  at  night.  This  symptom  has 
been  attributed  to  a  mild  neuritis. 

Ordinarily  digestive  symptoms  are  lacking.    One 
meets  occasionally  with  various  types  of  dyspeptic  dis- 


SYMPTOMATOLOGY  127 

turbances  but  these  are  not  characteristic.  The  tongue 
is  sometimes  coated;  more  frequently  red  and  dryish. 
The  teeth  are  very  prone  to  suffer  rapid  decay  in  dia- 
betes owing  perhaps  to  abstraction  of  the  lime  in  those 
cases  complicated  by  acidosis.  With  adults  there  is  a 
decided  tendency  to  contract  pyorrhoea  alveolaris, 
which  is  observed  generally  with  all  diabetics  in  hos- 
pital. Constipation  is  common,  due  to  loss  of  water 
from  the  intestine.  With  children  this  may  be  a  most 
distressing  and  difficult  symptom  to  combat. 

A  long  list  of  skin  disorders  have  been  more  or 
less  correctly  attributed  to  diabetes.  The  fact  that 
diabetics  usually  do  not  sweat  or  do  not  have  a  nor- 
mal amount  of  perspiration  may  be  the  reason  for  the 
dryness  of  the  skin  one  commonly  notes.  There  are 
observations  to  the  effect  that  the  sweat  and  tears  of 
diabetic  patients  contain  sugar ;  but  this  requires  con- 
firmation. Some  authors  have  held  that  psoriasis  is 
peculiarly  common  with  diabetics,  but  Naunyn  thinks 
the  association  accidental.  In  some  of  his  cases  the 
skin  lesion  antedated  the  glycosuria.  Among  other 
affections  of  the  skin  one  may  encounter  are  xan- 
thoma, chronic  urticaria,  and  impetigo.  The  fre- 
quency of  acne  is  in  some  measure  due  to  the  drugs 
commonly  employed  with  diabetes.  Among  the  older 
patients  eczema  is  almost  universal,  it  may  be  very  ex- 
tensive and  occasion  great  distress.    A  peculiar  itch- 


128  DIABETES  MELLITUS 

ing  of  the  skin  unassociated  with  any  visible  lesion  is 
sometimes  observed. 

Pruritus  vulvae  is  often  the  first  symptom  of  dia- 
betes in  women  who  have  passed  the  menopause.  The 
symptoms  result  from  irritating  urine  and  quickly 
subsides  if  the  sugar  excretion  is  controlled. 

Of  the  infections  of  the  skin  besides  acne,  boils 
and  carbuncles  are  common.  In  hospital  practice 
these  are  often  the  first  symptoms  which  prompt  the 
patient  to  seek  medical  aid.  With  carbuncle  in  an 
adult  patient  the  urine  should  always  be  tested  for 
sugar.  Less  met  with  is  perforating  ulcer  of  the  foot, 
malum  perforans  pedis.  It  is  encountered  usually  in 
old  subjects.  Apparently  it  may  be  a  diagnostic  pit- 
fall since  two  of  my  series  had  been  pronounced  tabetic 
on  account  of  the  ulcer  and  absence  of  knee  jerks. 

Diabetics  are  peculiarly  prone  to  nervous  disturb- 
ances. Besides  the  cramp-like  pains  in  the  legs,  al- 
ready referred  to,  a  frank  neuritis  is  often  seen.  This 
may  involve  any  nerve  trunk  but  is  more  usual  in 
those  of  the  lower  extremity.  The  neuritis  may  be  of 
either  the  sensory  or  motor  type.  A  woman  of  sixty 
suffered  from  neuritis  of  both  sensory  and  motor  type 
in  the  left  leg.  In  the  course  of  several  months  she 
became  free  of  pain  but  the  tibialis  anticus  muscle  was 
left  paralyzed.  A  year  later  the  same  sequence  of 
events  occurred  in  the  other  leg.     Neuritis  of  the 


SYMPTOMATOLOGY  129 

sensory  nerves  may  occasion  the  severest  pain  and  per- 
sist for  months.  In  these  disturbances  improvement 
in  the  diabetic  symptoms  is  not  always  followed  by 
an  amelioration  of  the  nervous  symptoms.  Absence  of 
the  patellar  reflex  is  also  to  be  regarded  as  a  neuritis. 
The  prognostic  significance  attached  by  some  members 
of  the  French  school  to  a  negative  Westphal  sign  is 
scarcely  warranted  by  facts.  This  sign  may  fail  early 
in  mild  cases  of  diabetes  and  is  usually  absent  in  those 
of  long  duration. 

An  interesting  symptom  is  intermittent  claudica- 
tion. It  is  scarcely  permissible  to  attribute  this  to  a 
neuritis;  it  is  possibly  secondary  to  anaemia  of  nerve 
centres  in  consequence  of  advanced  arteriosclerosis. 

Diabetic  patients  of  all  ages  may  suffer  from 
herpes  zoster;  but  I  have  met  with  it  most  often  in 
young  adults  and  children.  One  child,  a  girl  of  seven 
years,  experienced  two  attacks  in  a  period  of  six 
months.  The  pain  following  the  disappearance  of  the 
vesicles  is  fortunately  frequently  absent  with  children. 

It  is  not  clear  whether  impotence  is  to  be  regarded 
as  of  nervous  origin  or  is  an  effect  of  the  profound 
metabolic  disturbances.  This  symptom  is  occasionally 
among  the  earliest  indications  of  the  disease. 

Of  the  symptoms  related  to  the  eye,  cataract  is  by 
far  the  most  common.  Diabetic  retinitis  occurs  of  two 
types;  with  exudate  and  with  hemorrhage — centralis 


130  DIABETES  MELLITUS 

punctata,  and  hemorrhagica.  A  peculiar  sluggishness 
of  pupillary  reaction  to  light  has  been  described  by 
Grube  but  it  is  of  rare  occurrence. 

The  vulnerability  of  the  diabetic  patient  to  in- 
fection is  proverbial.  Whether  this  fact  be  due  to  the 
sugar  content  of  the  tissues,  as  some  believe,  or  whether 
the  fault  be  of  a  deeper  nature  had  best  be  left  an 
open  question.  Slight  wounds,  or  a  bruise,  may  be- 
come infected  and  result  in  a  lesion  dangerous  to  life. 
A  small  blister  on  the  foot  from  the  friction  of  a  new 
boot  causes  first  an  ulcer  and  then  osteomyelitis.  Some 
of  the  cases  of  gangrene  of  the  toes  have  this  origin. 
Not  so  many  are  neurogenic  as  is  supposed.  A  small 
percentage  are  probably  dependent  on  extreme  nar- 
rowing of  the  sclerosed  arteries  but  the  vast  majority 
are  infective. 

Likewise  the  vulnerability  of  the  mucous  mem- 
branes is  notable.  Cystitis  is  common,  also  chronic 
bronchitis  and  pulmonary  tuberculosis.  Colds  are 
contracted  with  ease;  pneumonia  is  usually  fatal. 
Pulmonary  gangrene  sometimes  develops  with  an 
acute  onset  and  signs  not  to  be  differentiated  in  the 
beginning  from  pneumonic  consolidation. 

Menstruation  usually  ceases  with  severe  cases  of 
diabetes.  Where  the  disease  is  less  profound  there  is 
irregularity  and  scantiness  of  flow.  Conception  is 
most  frequently  followed  by  early  abortion;  with  a 


SYMPTOMATOLOGY  131 

minority,  pregnancy  terminates  with  late  abortion; 
while  a  small  percentage  give  birth  to  living  children. 
Pregnancy  is  correctly  regarded  as  a  great  hazard  for 
a  diabetic  woman,  since  the  disease  is  sometimes 
rapidly  progressive  during  this  period  or  terminates  in 
death  shortly  after  delivery.  If  a  living  child  is  born 
the  chances  of  its  survival  are  much  diminished. 
Offergeld  *  noted  that  when  pregnancy  is  complicated 
by  diabetes  thirty  per  cent,  of  his  cases  died  in  coma 
before  the  completion  of  the  pregnancy  and  of  those 
that  survived  pregnancy  twenty-four  per  cent,  died 
within  thirty  months.  Hydramnios  occurred  in  ten  of 
his  sixty-three  cases.  Of  twenty-seven  children  born 
alive  but  fifteen  lived  longer  than  two  years.  It  is 
now  generally  believed  that  the  danger  of  pregnancy 
in  diabetes  is  comparable  to  that  in  patients  suffering 
from  tuberculosis  and  severe  valvular  disease.  Rarely 
it  does  happen  that  the  diabetes  is  less  severe  or  even 
vanishes  during  the  period  of  pregnancy.  A  woman 
whom  I  saw  in  consultation  was  in  better  general 
health  during  two  pregnancies  than  in  the  interval 
and  the  glycosuria  much  less.  She  is  still  alive  three 
years  after  the  last  pregnancy.  It  was  impossible  to 
demonstrate  with  this  patient  that  the  diabetes  was  of 
the  renal  type. 

The  urine  with  diabetes  presents  other  interesting 

1  Arch.  f.  Gynaekolog.,  1908,  Aug.  15,  p.  630. 


132  DIABETES  MELLITUS 

features  than  the  sugar.  The  excretion  of  the  latter 
may  be  almost  incredibly  large,  up  to  over  a  kilo  per 
day.  Exceptionally  the  sugar  is  not  all  glucose; 
levulose  has  been  found  in  a  few  cases  as  well  as 
dextrose.  The  urinary  volume  is  usually  above  nor- 
mal and  tends  to  be  roughly  in  proportion  to  the 
amount  of  sugar  excreted.  With  severe  cases  a  daily 
output  of  eight  or  ten  litres  is  not  uncommon  and  a 
volume  of  even  fifteen  litres  per  day  has  been  observed. 
Occasionally  a  considerable  diuresis  is  found  although 
the  sugar  excretion  may  be  relatively  small.  There 
is  in  this  respect  some  suggestion  of  a  diabetes  in- 
sipidus and  cases  of  this  latter  disease  complicating 
melituria  are  well  known.  The  percentage  of  sugar  in 
the  urine  may  be  small,  less  than  one,  yet  the  total 
glucose  output  for  each  day  may  be  25  to  50  grammes. 
This  serves  to  illustrate  the  fallacy  one  invites  if  the 
percentage  quantity  of  sugar  is  taken  as  a  guide  with- 
out respect  to  the  total  urine  volume  for  the  day. 
Fortunately  the  custom  is  almost  abandoned  in  this 
country  and  is  not  recognized  at  all  in  Europe.  The 
sugar  excretion  should  ever  be  estimated  as  grammes 
for  the  twenty-four  hours.  In  no  other  way  can  any- 
thing like  an  adequate  knowledge  of  the  patient's  con- 
ditions be  secured. 

Nitrogen  elimination  depends  on  the  protein  in- 
take ;  as  this  latter  is  usually  large  the  urinary  nitro- 


SYMPTOMATOLOGY  133 

gen  is  above  normal.  While  with  the  average  man 
the  total  nitrogen  in  the  urine  is  between  fifteen  and 
thirty  grammes,  the  diabetic  consumes  so  much  protein 
that  the  nitrogen  excretion  may  be  forty  or  even  fifty 
grammes  per  day.  With  a  few  severe  cases  where  the 
physician  had  ordered  meat  and  eggs  as  the  chief  in- 
gredients of  the  diet  I  have  noted  nitrogen  excretions 
of  some  fifty  grammes.  In  cases  where  the  protein 
ingest  is  restricted  and  the  nitrogen  elimination  ex- 
ceeds the  amount  taken  in,  the  difference  is  due  to  the 
catabolism  of  body  protein,  as  can  be  readily  demon- 
strated by  the  loss  in  body  weight. 

The  question  of  uric  acid  formation  and  its  possible 
destruction  in  the  normal  human  body  is  not  as  yet 
clearly  understood.  The  quantity  formed  depends 
certainly  on  two,  probably  on  three  factors;  the  most 
important  of  which  is  the  nuclein  ingested  in  the  food. 
Since  animal  foods  are  relatively  rich  in  nucleins, 
derived  from  the  nuclei  of  cells,  it  follows  that  the  uric 
acid  excreted  is  in  large  measure  proportionate  to  the 
amount  of  this  kind  of  food  eaten.  Diabetics  as  a 
class  eat  more  meat  than  normal  men  and  the  uric 
acid  excreted  is  consequently  above  the  average  nor- 
mal excretion.  It  is  not,  however,  out  of  propor- 
tion to  the  total  nitrogen  of  the  urine.  These  are 
factors  which  are  so  much  influenced  by  the  amount 
and  kind  of  diet  that  no  generalization  without  respect 


134  DIABETES  MELLITUS 

to  it  is  possible.  With  any  diet  of  definite  composition 
the  proportion  that  each  nitrogen  fraction — urea,  am- 
monia, etc. — bears  to  the  total  nitrogen  fluctuates  with- 
in narrow  limits  but  this  is  true  only  so  long  as  the  diet 
remains  unchanged  in  amount  and  composition.  With 
normal  man  on  a  mixed  diet  the  nitrogen  excreted  as 
urea  fluctuates  between  80  and  90  per  cent,  of  the 
total  nitrogen.  In  diabetes  so  long  as  there  is  no 
acidosis  the  normal  proportions  are  retained;  if  the 
total  nitrogen  be  thirty  grammes  about  ninety  per 
cent,  of  this  will  be  found  as  the  urea  nitrogen,  the  re- 
maining ten  per  cent,  is  composed  of  the  nitrogen  in 
ammonia,  creatinin,  uric  acid,  and  amino-acids. 
When,  however,  free  acids  are  elaborated  as  products 
of  metabolism  these  acids  are  in  part  neutralized  in 
compounds  with  ammonia  and  are  excreted  in  the 
urine  as  salts.  Ammonia  so  combined  with  acids  with- 
in the  body  does  not  of  course  arrive  at  its  normal  end- 
product,  urea.  This  is  shown  quite  clearly  in  the  urine 
of  acidosis  cases  in  that  the  urea  excretion  falls  while 
the  ammonia  nitrogen  increases.  Under  the  adminis- 
tration of  alkalies  to  the  patient  the  reverse  process 
ensues  and  in  mild  cases  of  acidosis  a  normal  nitrogen 
partition  may  be  effected.  The  normal  nitrogen  frac- 
tion excreted  as  ammonia  is  something  less  than  one 
gramme  per  day  and  under  any  condition  giving  rise 


SYMPTOMATOLOGY  135 

to  acidosis  this  figure  rises  considerably  and  is  a  valu- 
able index  to  the  degree  of  the  intoxication.  In  dia- 
betes one  frequently  finds  the  ammonia  nitrogen 
amounts  to  two  grammes  per  day  when  there  are  no 
evident  symptoms  of  acidosis.  When,  however,  this 
figure  rises  to  three  grammes  we  have  to  do  with  a 
condition  dangerous  to  the  patient.  It  is  then  an  in- 
dication for  alkaline  therapy  and  the  other  means  of 
combating  acid  intoxications.  An  excretion  of  four 
grammes  of  ammonia  nitrogen  daily  has  never  in  my 
experience  persisted  for  more  than  a  few  days  with- 
out the  development  of  coma.  During  the  period  of 
coma  the  ammonia  excretion  may  be  enormous,  espe- 
cially in  cases  where  there  has  been  no  administration 
of  alkalies.  Stadelmann  found  twelve  grammes  of  am- 
monia in  a  case  of  diabetic  coma.  In  a  similar  case 
admitted  to  hospital  in  coma  I  found  3.4  grammes  of 
ammonia  nitrogen  per  100  c.c.  of  urine  in  a  catheter- 
ized  specimen;  a  figure  that  would  indicate  10 
grammes  per  day  on  a  conservative  estimate  (3000 
c.c).  When  severe  acidosis  prevails  the  ammonia 
nitrogen  forms  a  high  per  cent,  of  the  total;  as  coma 
impends,  forty  or  even  fifty  per  cent,  of  the  total 
nitrogen  may  appear  in  the  urine  as  ammonia.  Under 
these  conditions  there  is  a  corresponding  fall  in  the 
nitrogen  excreted  in  the  form  of  urea. 


136  DIABETES  MELLITUS 

Until  recently  there  has  been  no  trustworthy 
method  for  estimations  of  the  amino- acid  content  of 
urine.  Several  methods  are  now  available  and  in  a 
short  while  our  knowledge  will  be  more  complete  in 
this  respect.  Employing  the  naphthalin  method, 
Abderhalden  found  appreciable  increases  over  nor- 
mal of  the  amino-acids  in  two  diabetic  urines.  One  of 
these  cases  suffered  from  a  terminal  pneumonia  and 
the  other  was  in  coma.  In  a  third  case  no  increase  was 
detected.2  An  increase  was  also  noted  in  the  urines  of 
deprancreatized  dogs  by  Labbe.  More  recently 
Loffler 3  has  examined  four  cases  employing  the  Van 
Slyke  method.  An  increased  amino-acid  output  was 
observed  in  all  and  this  was  most  marked  in  the 
severest  cases  of  diabetes.  Whereas  a  normal  output 
is  found  to  be  about  .1  gramme  per  day  in  severe  dia- 
betes the  figure  rises  to  0.26  or  even  0.7  grammes. 
The  significance  of  this  increase  is  not  clear  from  the 
data  at  hand.  It  suggests  some  profound  disturbance 
of  cellular  metabolism.  An  hypothesis  has  been  ad- 
vanced by  Hugounenq  that  the  terminal  coma  is  less  a 
consequence  of  the  abnormal  ketone  formation  than 
of  the  products  of  protein  disintegration.  Such  a 
view  lacks  adequate  basis  at  present. 

2  Zeit.  f .  physiol.  Chem,.,  1905,  44,  p.  17. 
"Loffler:  Zeit.  f.  klin.  Med.,  1913,  78,  p.  485. 


SYMPTOMATOLOGY 


1ST 


KETONE  BODIES 

The  presence  in  the  urine  of  acetone  and  /3-hy- 
droxybutyric  acid  is  by  no  means  characteristic  of  dia- 
betes. Small  amounts  of  acetone  are  normally  found, 
and  in  fevers  the  increase  is  considerable.  It  has  been 
repeatedly  observed  that  the  von  Laube  treatment  of 
gastric  ulcer  gives  rise  to  a  mild  acidosis  notable  in  a 
strongly  marked  Gerhardt's  reaction  in  the  urine  and 
detectable  amounts  of  acetone  and  hydroxybutyric 
acid.  Several  years  ago  when  fasting  was  in  vogue 
as  a  cure  for  all  ills  a  normal  man  abstained  from  all 
food  for  five  days.  The  urine  was  collected  for  me 
during  the  fourth  day  of  the  fast.    The  analysis  is: 


Amount. 

Total  N. 

NHs-N. 

Acetone  and 
diacetic  acid. 

/3-oxybutyric  acid. 

ex. 
1410 

gr. 
11.42 

gr- 
1.09 
(9.6%) 

gr. 
0.475 

gr. 
0.819 

The  grade  of  acidosis  represented  here  is  comparable 
to  that  found  in  mild  cases  of  acidosis  with  diabetes 
and  was  induced  in  this  case  purely  by  abstinence  from 
food.  Ketonuria  of  no  greater  severity  than  this 
occurs  in  many  conditions  and  is  seldom,  if  ever,  ac- 
companied by  symptoms  attributable  to  the  acidosis. 
Acetone  and  diacetic  acid  in  small  amounts  appear  in 
the  majority  of  diabetic  urines  at  some  period  during 


10 


138 


DIABETES  MELLITUS 


the  course  of  the  disease.  With  mild  cases  this  is  in- 
duced by  changes  in  diet  and  is  temporary;  in  other 
instances  the  ketone  bodies  vanish  along  with  the  dis- 
appearance of  the  sugar,  while  in  the  most  severe  dia- 
betes, it  is  noted  early  that  in  spite  of  all  means  to 
prevent  it  there  is  a  considerable  and  persistent  ex- 
cretion of  these  acids.  Very  large  amounts  may  be 
found  constantly  for  weeks  and  months  before  the 
onset  of  coma.  In  the  case  of  a  girl  of  nineteen  I 
found  constantly  between  five  and  six  grammes  of 
£-hydroxybutyric  acid  during  the  fourth  month  before 
coma.  These  figures  gradually  rose  as  the  end  ap- 
proached. The  following  table  gives  a  synopsis  of 
some  of  the  analyses  during  the  latter  months : 


Date. 

Urine. 

Sugar. 

Acetone 
diacetic. 

/3-oxybutyric. 

Nov.  20,  1908 

Dec.  1,  1908 

ex. 
7600 
7680 
8100 

gr. 
481 
530 
596 

gr. 

5.04 

6.87 

10.11 

gr. 
14.40 
22.45 

Feb.  5,  1909 

70.08 

Death  came  in  coma  Feb.  10. 

In  exceptional  cases  the  /?-oxybutyric  acid  ex- 
cretion may  be  as  much  as  150  grammes  per  day  dur- 
ing coma.4  Of  the  total  ketone  bodies  in  the  less 
severe  degrees  of  acidosis  the  larger  part  is  found  as 

4  Magnus-Levy:  Die  Oxybuttersaure  u.  ihre  Beziehungen  zum  Coma 
diabeticum,  Leipzig,   1899. 


SYMPTOMATOLOGY  139 

acetone  and  diacetic  acid.  As  the  acidosis  progresses 
and  gradually  becomes  more  and  more  pronounced 
there  is  an  ever-increasing  proportion  of  oxybutyric 
acid,  up  to  60  or  80  per  cent,  of  the  total  ketone  bodies, 
as  Neubauer 5  has  shown. 

COMA 

The  widest  variation  is  perceptible  among  dia- 
betic patients  in  their  resistance  to  acidosis.  Naunyn 
remarked  that  some  patients  appear  perfectly  com- 
fortable for  years  with  a  diurnal  excretion  of  twenty 
or  thirty  grammes  of  oxybutyric  acid.  On  the  other 
hand,  it  is  occasionally  noted  that  symptoms  commonly 
attributed  to  acid  intoxication  become  evident  when 
the  total  ketone  bodies  excreted  are  but  ten  or  fifteen 
grammes  per  day  although  the  alkaline  dosage  may 
be  sufficiently  large  to  secure  proper  elimination. 
For  of  course  it  is  to  be  recollected  that  it  is  the  re- 
tained acids  that  work  the  harm;  and  one  knows  that 
the  excretion  of  these  can  be  increased  considerably  if 
sufficient  alkali  be  administered. 

It  is  apparent  from  what  has  been  said  that  there 
are  to  be  found  in  the  urine  sufficient  data  to  warn  us 
of  dangerous  degrees  of  acidosis.  And  if  careful  and 
frequent  urine  examinations  be  made  coma  comes  in  a 
case  as  no  unforeseen  event.    Only  under  the  condi- 

6Verhandl.  d.  deutsch.  Congr.  inn.  Med.,  1910,  27,  p.  566. 


140  DIABETES  MELLITUS 

tions  where  it  is  anticipated  may  one  feel  that  all  that 
is  possible  has  been  done  to  prevent  it.  Diabetic  coma 
does  not  often  develop  suddenly  but  is  usually  pre- 
ceded by  several  days,  at  least,  of  fairly  characteristic 
symptoms.  The  patient  complains  of  cramps  in  the 
legs  and  abdomen  and  there  is  intolerable  lassitude. 
The  appetite  becomes  capricious  and  slight  nausea  is 
common.  Along  with  these  symptoms  there  is  usually 
some  headache,  which  is  attributed  to  obstinate  consti- 
pation. A  slight  oedema  of  the  ankles  is  often  detect- 
able. In  the  urine  one  may  find  a  fall  in  the  sugar 
output  with  high  values  for  ammonia  and  ketone 
bodies.  If  vigorous  treatment  be  employed  during 
this  stage  some  of  the  cases  can  be  carried  over  a 
dangerous  period  and  may  live  months  longer.  With 
many  all  means  at  our  command  are  of  no  avail.  The 
lassitude  is  followed  by  drowsiness  which  deepens 
gradually  into  profound  coma  from  which  the  patient 
cannot  be  roused.  After  the  prodromal  state  is  well 
marked  coma  may  develop  very  quickly.  In  one  case, 
a  young  woman,  there  had  been  disinclination  for 
exercise,  mental  torpor,  cramps  and  slight  gastric  dis- 
turbances for  three  days.  The  urine  had  shown  over 
three  grammes  of  ammonia  nitrogen  for  two  weeks 
and  50  grammes  of  soda  bicarbonate  and  citrate  had 
been  given,  which  was  later  increased  to  70  grammes 
daily.     On  the  fourth  day  the  patient  drove  for  an 


SYMPTOMATOLOGY  141 

hour  in  the  park  and  on  her  return  to  the  house  said 
she  felt  much  better.  She  rested  for  an  hour  before 
luncheon  but  felt  no  appetite  and  decided  to  go  to 
sleep.  At  three  o'clock  she  seemed  stuporous  and  the 
family,  having  been  warned,  appreciated  the  signifi- 
cance of  this  symptom  and  summoned  their  physician. 
In  the  evening  the  patient  was  in  profound  coma 
which  terminated  in  death  on  the  next  morning. 
Naunyn  and  others  have  reported  cases  where  the 
death  occurred  within  twelve  hours  after  the  first 
symptoms.  One  is  apt  to  forget  that  diabetes  may  be 
a  cause  of  sudden  death;  these  cases,  however,  are 
rare.  Although  death  in  coma  as  a  sequel  of  diabetes 
had  been  referred  to  by  Marsh,6  coma  diabeticum  was 
described  first  by  Kussmaul 7  and  to  the  clinical  pic- 
ture as  he  portrayed  it  little  if  anything  has  been 
added.  The  striking  feature  when  one  first  sees  the 
patient  is  the  type  of  respiration.  The  respiratory 
movements  are  long  and  deep,  involving  all  the 
muscles  and  suggest  in  the  inspiratory  phase  the  "long 
breath  that  precedes  a  yawn."  The  expiration  ap- 
pears more  complete  than  normal,  even  forced.  With 
this  there  may  be  increase  in  the  respiratory  rate 
which,  however,  is  usually  from  sixteen  to  twenty  per 
minute.    The  German  term  "Grosse  Atmung33  is  ex- 

e  Marsh:  Dublin  Quart.  Rev.,  1854,  13. 

7  Kussmaul:  Deutsch.  Archiv  f.  klin.  Med.,  1874,  xiv. 


142  DIABETES  MELLITUS 

actly  descriptive.  As  the  period  of  coma  lengthens 
there  is  commonly  noted  an  increase  in  the  respiratory 
rate  which  may  reach  to  40  per  minute  and  there  is 
then  no  evident  pause  between  inspiration  and  expira- 
tion. The  peculiarities  of  this  type  of  dyspnoea  dis- 
appear as  death  approaches.  In  no  other  disorder, 
save  a  few  cases  of  uraemia,  have  I  seen  exactly  the 
same  type  of  respiration  which  characterizes  Kuss- 
maul's  air  hunger. 

In  one  case  in  my  series  there  was  no  suggestion 
of  the  Kussmaul  air  hunger.  This  patient  gradually 
lapsed  into  coma  and  died  after  fifteen  hours.  The 
respirations  were  rapid  and  shallow  throughout  the 
coma  period.  Autopsy  failed  to  disclose  any  com- 
plication to  explain  the  atypical  symptoms.  Naunyn 
cites  two  cases  as  atypical  in  similar  respects  and  there 
are  eight  others  in  the  literature.8  Also  Cheyne- 
Stokes  respiration  may  alternate  with  typical  coma 
dyspnoea. 

As  to  the  mental  state,  it  is  dependent  upon  the 
duration  of  coma.  At  first  the  patient  can  be  roused 
and  is  mentally  clear ;  later,  however,  no  response  can 
be  elicited.  Delirium  should  excite  suspicion  as  to  the 
diagnosis. 

The  f acies  are  flushed,  often  with  a  cyanotic  tinge, 
and  one  may  be  deceived  in  the  appearance  of  fever. 

•Blum:  Ergebnisse  d.  inn.  Med.  u.  Kinderheilk.,  1913,  xi,  p.  445. 


SYMPTOMATOLOGY 


143 


The  temperature  rarely  rises  above  100°  F.  at  the 
onset  of  coma  and  gradually  falls  until  death;  it  is 
often  subnormal  and  has  been  recorded  as  low  as 
90°  F. 


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Several  observations  relating  to  the  eyes  are  of 
diagnostic  moment.  The  pupils  are  sometimes  dilated, 
less  often  slightly  contracted,  and  the  light  reflex  is 
retained  until  late.  Krause  called  attention  to  a  pecu- 
liar softening  of  the  eyeball  which  Schiitz  has  shown 
to  be  due  to  a  diminution  of  intraocular  pressure. 


144  DIABETES  MELLITUS 

This  seems  to  be  a  very  constant  phenomenon  which  I 
have  noted  in  all  cases.  On  the  other  hand,  I  have 
never  observed  Loewi's  mydriasis  after  applications 
of  adrenalin.  The  vessels  of  the  fundus  may  assume  a 
peculiar  whitish  appearance  in  cases  where  there  is  a 
high  degree  of  lipaemia.    This,  however,  is  variable. 

Some  acceleration  of  the  pulse  is  the  rule,  but  a 
rate  above  120  per  minute  is  exceptional.  The  pulse 
is  verjT  soft,  and  the  blood-pressure  falls  as  the  coma 
period  advances. 

In  many  cases  a  slight  oedema  can  be  made  out 
over  the  ankles. 

This  typical  coma  is  observed  in  the  great  majority 
of  instances.  In  a  small  percentage  the  picture  is 
different  hi  some  essential  respects.  It  is  an  open 
question  with  these  atypical  cases  if  we  have  really  to 
do  with  coma  diabeticum  but  as  yet  no  differentiation 
can  be  made  founded  on  causation.  The  chief  varia- 
tions relate  to  the  type  of  respiration.  In  some  of 
these  cases  the  ketone  bodies  excreted  in  the  urine  have 
been  relatively  of  low  amounts.  In  others  the  cardiac 
weakness  dominates  the  picture.  The  pulse  is  rapid, 
140  to  160,  and  the  heart  sounds  barely  audible.  In 
one  of  French's  cases  there  was  no  peculiarity  of 
respiration  but  notable  cardiac  weakness;  and  von 
Xoorden's  case  died  before  deep  coma  prevailed,  ap- 
parently from  cardiac  failure. 


SYMPTOMATOLOGY  145 

A  few  cases  are  reported  in  the  literature  where 
coma  has  been  ushered  in  by  convulsions.9  This  is  an 
exceedingly  rare  complication  and  in  any  event 
uraemia  must  be  regarded  as  a  possible  explanation. 
Naunyn  in  his  enormous  experience  has  not  encoun- 
tered such  a  case.  Janowski  suggests  that  convul- 
sions with  diabetic  coma  are  peculiarly  common 
among  the  Poles. 

Coma  may  develop  with  scarcely  any  warning  dur- 
ing convalescence  from  infectious  diseases.  With  two 
cases  of  pneumonia  and  one  of  erysipelas  I  have  ob- 
served this  termination.  A  man  of  forty-two  had 
been  under  medical  supervision  for  four  years  on  ac- 
count of  a  mild  diabetes.  In  March,  1908,  he  con- 
tracted pneumonia.  The  infection  did  not  appear  to 
be  a  severe  one  but  considerable  apprehension  was 
felt  for  him  because  of  the  diabetes.  Defervescence 
by  crisis  occurred  on  the  sixth  day  of  the  disease  and 
on  the  seventh  and  eighth  days  the  patient's  condition 
was  excellent.  The  urine  besides  sugar  contained  a 
trace  of  albumin  and  many  casts.  There  was  no 
Gerhardt's  reaction  but  a  strong  acetone  reaction.  On 
the  ninth  day  some  nausea  was  experienced  during  the 
forenoon  and  the  patient  complained  of  breathlessness. 
Careful  physical  examination  indicated  a  resolving 
pneumonia,  nothing  else.    The  afternoon  of  the  same 

9Losson:  Zeit.  f.  klin.  Med.,  1908,  p.  56. 


146  DIABETES  MELLITUS 

day  when  I  first  saw  the  patient  there  was  quite 
typical  air  hunger ;  sopor  was  marked  but  the  patient 
could  be  roused  to  answer  questions.  There  was  noth- 
ing in  the  physical  examination  of  significance.  The 
temperature  was  98.2°  F.,  the  pulse  90  per  minute. 
A  small  specimen  of  urine  was  examined  and  found  to 
be  very  acid:  specific  gravity  1032;  sugar  1.3  per 
cent.;  albumin,  heavy  trace;  ammonia  N,  0.32 
gramme  per  cent.;  total  N,  1.9  grammes  per  cent.; 
diacetic  and  /?-oxybutyric  acids  present.  The  patient 
was  given  soda  bicarbonate  by  mouth  and  by  enemata 
and  30  grammes  of  sodium  carbonate  intravenously, 
without,  however,  improving  his  condition.  Death 
occurred  on  the  afternoon  of  the  tenth  day  of  his  sick- 
ness, following  deep  coma. 

In  the  other  case  of  pneumonia  a  similar  sequence 
of  events  occurred. 

With  reference  to  the  case  of  erysipelas  the  facts 
may  be  briefly  summarized.  This  patient,  a  man  of 
fifty,  had  been  in  New  York  Hospital  for  two  weeks 
under  treatment  for  a  moderately  severe  diabetes. 
When  he  developed  facial  erysipelas  it  was  expected 
he  would  quickly  succumb.  He  was  transferred  to  the 
isolation  ward  and  to  the  astonishment  of  all  concerned 
with  him  after  ten  days'  sickness  he  began  to  improve 
rapidly.  The  sole  untoward  symptom  was  a  marked 
ketonuria  which  he  had  had  since  admission.    After 


SYMPTOMATOLOGY  147 

three  days  of  normal  temperature  and  marked  gain 
in  his  general  condition,  air  hunger  developed.  Coma 
followed  rapidly  and  the  patient  died  in  twelve  hours 
after  its  onset. 

When  the  patient  has  been  under  observation  and 
the  signs  of  acidosis  recognized  the  diagnosis  of  dia- 
betic coma  offers  no  difficulty.     When,  however,  a 
comatose  patient  is  brought  to  the  hospital  with  no 
history  and  sugar  is  found  in  the  urine  considerable 
confusion  may  arise  in  differentiating  coma  diabeti- 
cum  from  some  other  conditions.     It  is  to  be  re- 
membered that  uraemia,  apoplexy,  and  meningitis  are 
frequently  terminal  events  in  diabetes.     Moreover, 
any  disease  giving  rise  to  coma  may  occur  as  a  com- 
plication in  diabetes.    The  condition  most  commonly 
mistaken  for  diabetic  coma  is  uraemia.    With  diabetic 
individuals  over  fifty  years  of  age  uraemia  is  often  the 
cause  of  death.    The  fact  has  been  frequently  alluded 
to  that  a  glycosuria  of  long  standing  may  diminish  or 
become  intermittent  and  with  such  cases  there  is  very 
often  a  marked  increase  in  blood-pressure  and  retinal 
hemorrhages.    The  type  of  respiration  usually  found 
with  uraemia  has  in  it  nothing  suggesting  Kussmaul's 
air  hunger;  neither  does  the  urine  give  evidence  of 
marked  acidosis.    When  mistakes  in  diagnosis  occur 
they  are  due  to  the  fact  that  sugar  in  the  urine  is  re- 
garded as  pathognomonic  and  all  other  evidence  dis- 


148  DIABETES  MELLITUS 

regarded.  Sugar  may  occur  in  the  urine  temporarily 
in  a  long  series  of  morbid  states;  marked  ketonuria 
with  high  ammonia  values  very  seldom.  The  follow- 
ing case  is  one  of  three  wherein  ursemic  coma  was  not 
recognized. 

A  woman  sixty-two  years  of  age  had  been  under 
treatment  since  1899  for  a  mild  diabetes.  Sugar  dis- 
appeared from  the  urine  so  long  as  she  employed  the 
diet  her  physician  advised.  In  1904  she  found  that 
her  urine  reports  showed  no  sugar  although  she  was 
not  restricting  her  diet  except  in  avoiding  sugar.  In 
1905  she  suffered  from  neuritis  in  the  left  arm  and  her 
blood-pressure  was  then  190  mm.  mercury.  During 
the  spring  of  1910  there  were  severe  headaches  and 
considerable  loss  in  weight.  The  urine  was  examined 
at  irregular  intervals  and  was  usually  free  of  sugar, 
although  small  amounts,  less  than  one  per  cent.,  were 
noted  on  a  couple  of  examinations.  In  December, 
1911,  following  several  days  of  extremely  severe  head- 
aches associated  with  nausea  and  slight  vomiting,  the 
patient  became  stuporous  and  finally  comatose.  The 
examination  of  urine  showed  a  trace  of  albumin  and 
sugar  present  (estimation  not  done) ,  a  moderate  num- 
ber of  hyaline  and  granular  casts,  and  a  specific  gravity 
1023.  The  diagnosis  of  diabetic  coma  was  made  and 
advice  sought.    On  examination  the  respiratory  move- 


SYMPTOMATOLOGY  149 

ments  were  nearly  normal.  There  was  notable  car- 
diac hypertrophy,  a  blood-pressure  of  264  mm.  mer- 
cury, albuminuric  retinitis,  intra-ocular  pressure  not 
reduced.  The  urine  was  not  highly  acid  and  contained 
a  trace  of  acetone,  but  no  diacetic  nor  oxybutyric  acids. 
The  patient  recovered  from  this  attack  of  uraemia  and 
lived  eight  months.  Death  was  due  to  typical  uraemic 
coma.  The  respiratory  movements  in  uraemia  are  very 
exceptionally  of  the  Kussmaul  type ;  the  coma  not  so 
deep  and  slight  delirium  or  disorientation  is  at  least 
common.  Moreover  there  is  commonly  slight  fever 
and  a  leucocytosis.  The  ketonuria  when  present  is 
of  trifling  grades  resulting  from  restricted  food  in- 
gest, and  the  urinary  ammonia  is  never  very  high. 
With  uraemia  the  urine  is  also  quickly  made  alkaline 
by  the  administration  of  alkalies,  a  condition  which  is 
very  difficult  to  bring  about  with  diabetic  coma.  When 
it  is  possible  to  do  so  an  estimation  of  the  sugar  and 
non-protein  nitrogen  in  the  blood  may  determine  the 
diagnosis. 

The  glycosuria  occasioned  by  fracture  of  the  skull, 
hemorrhage  in  the  medulla  or  pons,  will  never  lead  to 
error  in  diagnosis  if  proper  examination  of  the  patient 
be  made.  On  the  contrary,  sugar  in  the  urine  is  at 
times  a  useful  aid  in  correctly  interpreting  the  other 
signs. 


150  DIABETES  MELLITUS 

COMA  THEORIES 

There  remain  for  consideration  the  theories  which 
have  been  advanced  to  explain  the  train  of  symptoms 
we  recognize  as  diabetic  coma.  The  older  conception 
advocated  by  Naunyn  and  based  upon  the  experi- 
mental work  of  Stadelmann  is  that  of  an  acidosis.  By 
this  it  is  to  be  understood  that  some  acid  induces  symp- 
toms which  are  analogous  to  the  artificial  coma  that 
may  arise  in  animals  if  large  amounts  of  acids  be 
administered.  This  conception  stands  in  contrast  to 
the  second  theory  that  views  coma  as  the  effect  of  a 
specific  toxin  which  in  this  case  happens  to  be  of  acid 
properties.  Now  what  are  the  criteria  as  we  under- 
stand them  of  acidosis?  If  acids  are  produced  in  large 
amounts  in  the  tissues  four  effects  are  noted:  (1)  A 
highly  acid  urine  not  readily  made  neutral  or  alkaline 
by  administering  alkalies;  (2)  a  marked  increase  in 
the  ammonia  of  the  urine;  (3)  decreased  carbon 
dioxide  content  of  the  blood  and  of  the  alveolar  air; 
(4)  increase  in  hydrogen  ion  concentration  of  the 
blood;  i.e.,  the  blood  is  less  "alkaline"  than  normally. 
Some  or  all  of  these  criteria  for  the  establishment  of  a 
condition  of  acidosis  are  found  in  many  morbid  states, 
as  for  example,  in  the  removal  of  carbohydrates  from 
the  diet,  starvation,  fevers,  and  disturbances  in  circula- 
tion.10    In  these  conditions  symptoms  do  not  attend 

10  Palmer  and  Henderson:  Arch.  Int.  Med.,  1913,  12,  p.  153. 


SYMPTOMATOLOGY  151 

the  mild  degree  of  acidosis  observed.    In  diabetes  of 
the  severest  types  and  in  coma  there  is  always  observed 
a  marked  increase  in  the  ammonia  of  the  urine  and 
usually  a  decrease  in  the  carbon  dioxide  content  of  the 
blood  and  alveolar  air.11     The  urine  in  coma  is  so 
highly  acid  that  an  amphoteric  reaction  is  effected 
only  after  the  ingestion  of  large  amounts  (100-200 
grammes)  of  bicarbonate  of  soda,    In  some  cases  at 
least12    there    has    been    found    by    electrochemical 
methods  an  increase  of  hydrogen  ions  in  the  blood, 
and  by  the  less  accurate  titration  methods  an  alkaline 
decrease.    What  then  are  the  objections  to  the  theory 
of  acidosis  since  the  criteria  are  apparently  fulfilled  in 
some  of  the  cases  of  diabetic  coma?    It  is  usually  ob- 
jected that  alkalies  fail  of  effect  with  the  majority 
of  cases  of  coma.    That  alkalies  are  not  curatives  with 
many  cases  is  doubtless  true  but  it  must  be  granted  to 
advocates  of  the  theory  that  the  amount  required  is 
almost  impossible  to  administer.    With  but  one  possi- 
ble exception  there  are  no  fatal  cases  on  record  where 
the  urine  has  successfully  been  rendered  alkaline  and 
in  this  instance  the  patient  succumbed  to  the  attack. 
The  single  exception  mentioned  is  a  case  of  Ehrman's 
and  valid  objections  have  been  raised  to  this  example.13 
When  one  considers  the  enormous  amounts  of  /?-oxy- 

"Porges:  Wiener  klin.  Wochenschr.,  1911,  22. 

*  Strauss:  Deut.  Arch.  f.  klin.  Med.,  1913,  109,  p.  3. 

13  Blum :  loc.  cit. 


152  DIABETES  MELLITUS 

butyric  acid  that  accumulates  in  the  tissues  during 
coma  it  is  not  surprising  that  alkali  therapy  often  fails. 
Magnus-Levy  recovered  from  the  tissues  of  patients 
dying  in  coma  150  to  200  grammes  of  oxybutyric  acid; 
an  amount  which  if  reckoned  per  kilo  body  weight  is  as 
much  as  Walter  used  to  induce  coma  in  rabbits.  In 
order  to  neutralize  this  and  effect  its  elimination  there 
would  be  required  200  to  300  grammes  of  bicarbonate 
of  soda.  Moreover,  in  this  state  the  production  of 
acids  goes  on  constantly.  A  case  of  Magnus-Levy,  a 
boy  weighing  but  30  kilos,  recovered  from  coma  after 
having  received  about  200  grammes  of  soda  bicarbo- 
nate during  24  hours.  The  total  ketone  elimination  in 
the  urine  during  this  day  was  160  grammes.  As  Blum 
has  said,  the  failure  of  alkali  therapy  to  cure  is  quite  as 
much  in  support  of  the  acidosis  theory  as  against  it  so 
long  as  enormous  dosage  does  not  result  in  alkaline 
urine.  The  crucial  evidence  against  the  acidosis 
theory  rests  on  showing  that  cases  die  in  coma  fol- 
lowing the  successful  administration  of  sufficient  alkali 
to  secure  alkaline  urine.  This  evidence  is  lacking. 
On  the  contrary  there  is  a  considerable  evidence  to 
attest  the  fact  that  even  with  cases  that  terminate 
fatally  there  is  marked  temporary  improvement  fol- 
lowing large  doses  of  alkalies.14 

The  acidosis  theory  of  Stadelmann  and  Naunyn 

w  Hanssen:  Zeit  f.  klin.  Med.,  1912,  76,  p.  219. 


SYMPTOMATOLOGY  153 

has  not  met  with  the  approval  of  Ehrman,  who  re- 
gards the  symptoms  of  coma  diabeticum  as  due  to  the 
toxic  properties  of  acids  in  contrast  to  their  acid  prop- 
erties since  the  salts  are  alkaline.  The  question  then 
arises  which  of  the  many  fatty  acids  that  might  occur 
in  this  state  of  morbid  metabolism  is  sufficiently  poison- 
ous to  induce  symptoms?  Von  Noorden,  who  has  sup- 
ported Ehrman's  hypothesis,  contends  that  oxybutyric 
acid  is  toxic.  Of  the  ketone  bodies  acetone  does  not 
come  into  consideration,  since  it  results  from  spontane- 
ous breakdown  of  diacetic  acid,  which  is  more  toxic  than 
oxybutyric  acid.  When  administered  as  its  sodium 
salt  oxybutyric  acid  is  not  more  toxic  than  acetic  acid. 
In  his  earlier  paper  Ehrman  15  contended  that  the 
toxic  acid  is  butyric.  When  this  acid  is  given  in  the 
form  of  a  sodium  salt  to  cats  and  puppies  it  induces 
coma,  air  hunger,  and  diminished  intra-ocular  pres- 
sure, characteristic  of  coma  in  diabetes.  With  other 
acids  employed,  propionic,  valerianic  and  isobutyric, 
the  effects  were  much  less  pronounced,  hence  Ehrman 
concluded  that  butyric  is  the  specific  acid.  Butyric 
acid,  however,  has  not  been  isolated  in  appreciable 
amounts  from  the  urine  or  tissues  of  coma  cases,  and, 
while  it  might  be  contended  that  butyric  acid  is  too 
easily  transformed  into  its  catabolic  derivatives  to  be 
detected  in  the  tissues,  this  argument  in  itself  could 

■  Ehrman:  Zeit  f.  klin,  Med.,  1911,  72. 
11 


154  DIABETES  MELLITUS 

be  used  against  Ehrman's  hypothesis.  In  his  most 
recent  contribution  this  investigator  appears  to  have 
abandoned  butyric  acid  since  observing  that  a  typical 
coma  may  be  produced  in  rabbits  by  means  of  oxy- 
butyric  combined  with  diacetic  acid.  This  coma  he  be- 
lieves due  to  the  toxic  properties  of  these  acids  since 
the  symptoms  noted  depend  on  the  amount  of  acids 
in  relation  to  the  weight  of  the  brain  rather  than  in 
relation  to  body  weight.16  Considering  the  numerous 
sources  of  possible  error  in  experiments  conducted  in 
this  manner  one  cannot  be  deeply  impressed  with  the 
finality  of  the  results.  Ehrman's  hypothesis  may  be 
true  but  it  rests  at  present  on  insecure  foundations. 

There  are  two  sources  of  weakness  in  the  acidosis 
theory  of  coma;  one  is  that  the  acids  concerned  exist 
in  the  tissues,  we  must  assume,  not  as  free  acids  but 
as  salts  in  combination  with  sodium,  potassium,  am- 
monium, etc.,  but  these  salts  are  not  acid  but  possess 
alkaline  properties  as  Ehrman  pointed  out.  The 
second  weakness  in  the  theory  is  that  the  blood  in 
cases  of  diabetic  coma  does  not  invariably  show  pre- 
ponderance of  hydrogen  ions.  The  blood  is  not  less 
"  alkaline  "  than  normal.  Of  eleven  cases  examined 
by  means  of  the  electrochemical  method  Roily  17  found 
the  H  ions  increased  in  but  three.    If  further  investi- 

18  Ehrman:  Berlin,  klin.  Wochenschr.,  1913,  No.  2,  Jan.  13. 
17  Roily:  Mediz.  Klinik,  1913,  ix,  Apr.  13.    Miinch.  med.  Wochenschr., 
1912,  59,  p.  1201. 


SYMPTOMATOLOGY  155 

gation  substantiates  Roily' s  observation  some  changes 
in  our  conception  of  coma  will  be  imperative.  There 
is  room  for  a  conception  of  acidosis  that  has  not  been 
touched  upon.  The  distinction  between  whether  an 
acid  is  injurious  because  of  its  inherent  toxic  proper- 
ties or  simply  because  it  is  an  acid  becomes  a  very  nice 
one  when  we  deal  with  acids  the  salts  of  which  are  not 
themselves  poisonous.  It  is  conceivable  that  an  acid 
not  toxic  in  itself  nor  forming  salts  which  are  toxic 
might  produce  toxic  effects  nevertheless.  It  is  well 
known  that  in  the  fluids  of  the  body  there  is  a  certain 
relation  maintained  between  the  various  bases,  sodium, 
potassium,  etc.  In  effect  the  withdrawal  of  one  of  these 
is  equivalent  to  a  surplus  of  bases  left.  Dennstedt 18 
found  in  the  ash  analysis  of  blood  and  tissues  of  dia- 
betic cases  less  sodium  than  normal,  and  this  fact  is 
the  more  striking  since  large  amounts  of  sodium  bi- 
carbonate had  been  administered  to  these  patients. 
The  potassium  was  increased.  These  results  suggest 
a  selective  action  on  the  part  of  the  acids  for  a  certain 
base,  sodium,  which  in  effect  and  actually  results  in  a 
preponderance  of  others.  It  is  possible  that  in  the 
disturbance  of  some  delicate  adjustment  such  as  is 
this  will  be  found  the  explanation  of  those  cases  of 
coma  that  do  not  show  an  excess  of  hydrogen  ions  in 
the  blood. 

"Dennstedt:  Mitteilung  aus   d.   Hamburg  Staatskrankenanstallten, 
1900,  3,  1;  Zeit.  f.  klin.  Med.,  1905,  58,  84. 


X 

RENAL  DIABETES 

There  are  on  record  a  number  of  cases  of  gly- 
cosuria attributed  to  increased  permeability  of  the 
kidney — renal  diabetes.  The  features  that  first  at- 
tracted attention  to  this  anomaly  and  suggested  that 
the  disorder  is  not  a  true  diabetes  are  that  the  amount 
of  sugar  excreted  is  but  little  or  not  at  all  influenced 
by  the  amount  of  carbohydrate  ingested;  and  also 
that  these  individuals  present  none  of  the  typical  dia- 
betic symptoms.  A  more  careful  study  of  these  cases 
has  also  disclosed  the  fact  that  the  amount  of  blood 
sugar  is  within  the  physiological  limits — not  over  0.1 
per  cent.  A  certain  conservatism,  if  not  skepticism, 
prevails  regarding  the  nature  of  these  cases  of  so- 
called  renal  diabetes,  and  under  close  scrutiny  but 
very  few  of  those  recorded  can  escape  the  suspicion 
that  they  are  early  manifestations  of  diabetes  mellitus. 
The  ultimate  criterion  according  to  our  present  knowl- 
edge is  the  blood  sugar  and  until  recently  the  methods 
of  analysis  gave  ample  chance  for  error  in  these  esti- 
mations. Two  cases  that  meet  with  the  necessary  re- 
quirements for  differentiation  may  be  cited.  The 
first,  reported  by  Bonniger,1  is  that  of  an  alcoholic 

1  Deutsch.  med.  Wochenschr.,  1908,  p.  780. 
156 


RENAL  DIABETES  157 

man  thirty-seven  years  of  age.  The  sugar  excretion 
of  0.2  per  cent,  on  an  ordinary  diet  was  not  influenced 
by  the  strictest  carbohydrate-free  diet,  neither  was 
it  influenced  by  the  addition  of  100  grammes  of  glucose 
to  a  diet  rich  in  starch.  In  addition  it  was  found  that 
the  glucose  excretion  bore  no  relation  to  meals.  The 
blood  analyses  showed  that  the  sugar  varied  from 
0.097  to  0.062  per  cent.,  while  the  urinary  excretion 
of  glucose  fluctuated  from  .2  to  .5  per  cent.  Tachau's 
case  entered  the  hospital  on  account  of  diarrhoea.  The 
sugar  excretion  was  always  less  than  one  per  cent, 
and  at  times  this  disappeared  on  ordinary  diet.  There 
was  no  increase  of  sugar  elimination  after  ingesting 
100  grammes  of  dextrose  and  hyperglycemia  was  not 
found  throughout  the  period  of  observation.2  More 
recently  a  renewed  interest  has  been  awakened  in  the 
subject  on  account  of  the  relation  it  holds  with  some 
cases  of  glycosuria  during  pregnancy.  The  frequency 
of  sugar  excretion  during  this  period  has  been  re- 
marked by  numerous  observers,  notably  von  Jaksch 
and  Bergsma.  Naunyn  regarded  the  condition  as 
pathological  and  Hofbauer  believed  the  fault  de- 
pended on  hepatic  function.  A  more  careful  study 
of  these  instances  of  pregnancy  glycosuria  has  dis- 
closed that  while  with  a  small  percentage  the  sugar 
excretion  represents  the  inception  of  true  diabetes, 

aDeut.  Arch,  f,  klin,  Med.,  1911,  104,  p.  448. 


158  DIABETES  MELLITUS 

with  the  majority  this  is  not  the  case.  The  glycosuria 
may  recur  during  several  pregnancies  while  during 
the  intervals  the  urine  is  normal.  Moreover  the  sugar 
excretion  presents  all  of  the  characteristics  that  con- 
note renal  diabetes:  the  amount  of  sugar  excreted  is 
relatively  slight,  6  to  15  grammes  per  day,  and  varies 
considerably  irrespective  of  the  diet  and  there  are  none 
of  the  symptoms  associated  with  true  diabetes.  The 
blood  sugar  is  normal  or  low.3  The  explanation  that 
has  been  suggested  is  that  the  renal  cells  are  hyper- 
sensitive to  glucose.4 

8  Mann:  Zeit.  f.  klin.  Med.,  1913,  78,  p.  488.     Frank:  Arch.  f.  exp. 
Pathol,  u.  Pharmakol.,  1913,  72,  p.  387. 

4  Novak,  Porges,  and  Strisover:  Zeit.  f.  klin.  Med.,  1913,  78,  p.  4.13. 


XI 

DIAGNOSIS   AND   CONSIDERATIONS 

WHICH  AFFECT  THE  COURSE 

OF  THE  DISEASE 

The  significant  feature  of  diabetes  mellitus  is  a 
glycosuria  which  is  constantly  present  on  a  normal 
diet.  Glycosurias  due  to  excessive  amounts  of  food,  to 
alcohol,  and  many  other  causes  that  have  been  already 
referred  to  are  excluded  from  the  category  of  dia- 
betes by  the  transitory  nature  of  the  sugar  excretion. 
Doubtless  many  instances  of  intermittent  glycosuria 
represent  an  initial  stage  of  diabetes,  but  on  the  other 
hand,  it  is  equally  certain  that  all  do  not.  With  re- 
gard to  the  class  of  persistent  glycosurias,  diabetes, 
it  seems  most  probable  that  there  we  meet  only  a 
single  common  symptom,  the  sugar  excretion,  depend- 
ent on  several  causes.  Certainly  the  clinical  picture 
of  diabetes  in  a  child  with  its  fearful  rapidity  and  the 
almost  immediate  development  of  acidosis  leading  to 
death  in  a  few  months  has  very  little  in  common  with 
the  slow  benign  course  of  the  malady  in  elderly 
adults.  Other  discrepancies  in  the  unity  of  the  dis- 
ease have  often  been  emphasized  and  classifications 
have  been  suggested  but  none  has  withstood  criticism. 
Tests  that  we  may  apply  during  life  are  lacking  and 

159 


160  DIABETES  MELLITUS 

morbid  anatomy  fails  to  disclose  a  constant  etiology. 
Until  these  deficiencies  in  our  knowledge  are  filled  we 
are  forced  to  group  together — because  of  certain  simi- 
larities in  symptoms  and  a  few  constant  signs — several 
disease  types. 

While  it  may  not  be  evident  at  once  with  every 
case  what  the  course  of  the  diabetes  will  be,  a  little 
study  and  observation  is  usually  sufficient  to  enable 
one  to  assign  an  individual  case  to  certain  broad  group- 
ings without  respect  to  the  etiological  factors  involved 
so  much  as  with  regard  to  the  course  and  progress  of 
the  disease. 

With  children  and  young  adults  the  progress  and 
termination  of  diabetes  may  be  seen  definitely.  The 
children  all  succumb  within  a  comparatively  short 
period  after  the  disease  is  recognized ;  two  years  from 
the  time  of  the  first  symptoms  is  the  longest  tenure 
that  has  come  to  my  observation.  I  have  known  of  no 
case  of  recovery.  Naunyn  mentions  a  four  year  old 
girl  who  for  a  period  of  three  weeks  (November  27  to 
December  13)  excreted  two  to  five  per  cent,  of  glu- 
cose. No  sugar  was  ever  found  subsequently  and  the 
child  grew  to  a  healthy  woman.  The  attack  of  gly- 
cosuria followed  acute  gastritis.  Naunyn  cites  this 
case  with  all  reserve  and  does  not  seem  to  regard  the 
recovery  as  due  to  any  therapeutic  means  employed. 
These  instances  are  of  such  excessive  rarity  that  they 


DIAGNOSIS  AND  CONSIDERATIONS  161 

extend  no  ground  for  optimistic  prognosis.  The  prog- 
nosis in  regard  to  length  of  life  with  adolescent  indi- 
viduals is  very  uncertain  for  these  reasons:  In  the 
beginning,  the  disease  is  often  but  moderately  severe, 
occasionally  even  light;  the  glucose  may  vanish  with 
strict  diet  or  is  controlled  to  a  small  daily  output; 
there  is  no  acidosis  and  it  is  not  difficult  to  maintain 
good  nutrition.  This  condition  of  affairs  may  persist 
for  months  without  change  and  the  family,  and  per- 
haps also  the  physician,  are  deceived  by  appearances. 
Sooner  or  later,  however,  there  comes  a  change  and 
this  change  is  often  very  sudden.  The  glycosuria  is 
now  severe  and  is  difficult  to  influence  by  diet  and 
what  is  worse  the  urine  gives  the  reactions  for  ketone 
bodies.  In  a  word  the  patient  has  developed  the 
severest  type  of  diabetes.  From  this  time  on  it  is  a 
death  struggle  with  acidosis.  It  is  impossible  to  fore- 
see how  long  a  period  will  elapse  before  this  latter 
final  stage  of  the  disease  becomes  manifested.  With 
some  cases  it  is  five  or  six  years,  with  others  only  a 
matter  of  months.  Since  prolongation  of  the  less 
severe  period  is  influenced  considerably  by  watchful 
observation  and  appreciation  of  the  significance  of 
seemingly  trivial  details  in  the  urine  analyses  and  the 
condition  of  the  patient,  too  much  emphasis  cannot  be 
placed  upon  their  necessity.  The  advent  of  the  second 
or  severe  phase  leaves  only  too  little  that  may  be  done 


162  DIABETES  MELLITUS 

to  lengthen  life.  With  many,  however,  the  disease  is 
not  recognized  until  acidosis  is  pronounced  and  the  end 
already  in  sight.  Of  the  cases  of  diabetes  before  the 
second  decade,  with  the  great  majority  death  is  due  to 
coma.  Coma  has  been  the  direct  cause  of  death  of  all 
of  the  cases  of  this  class  that  I  have  treated  or  seen  in 
consultation.  In  some  instances  the  fatal  acidosis  was 
aggravated  by  slight  infections,  such  as  tonsillitis,  in- 
fluenza, and  in  one  case  by  measles.  It  is  also  to  be 
noted  that  the  sugar  excretion  with  these  individuals 
increases  during  the  period  of  an  infection  which  is  in 
contrast  to  the  findings  with  milder  types  of  the  malady. 
The  relation  of  comparatively  slight  intercurrent 
infections  to  the  diabetes  is  often  remarkable.  The 
fact  that  these  patients  are  prone  to  infections  is  well 
known,  but  what  is  referred  to  here  is  the  effect  of  the 
febrile  period  on  the  diabetes  and  this  is  especially 
manifest  with  young  persons.  It  happens  quite  often 
that  following  a  sharp  attack  of  influenza  or  tonsillitis 
there  is  noted  at  once  a  marked  increase  in  the  sugar 
output  and  upon  investigation  it  is  discovered  that  the 
patient  can  no  longer  utilize  the  same  amount  of  car- 
bohydrate that  he  did  previous  to  his  fever.  With 
the  smaller  fraction  of  the  cases  careful  regulation  of 
the  diet  may  restore  the  lost  ground,  with  many  the 
loss  is  irreparable.  This  is  often  the  crucial  period 
when  a  diabetes  heretofore  tractable  takes  on  its  worst 


DIAGNOSIS  AND  CONSIDERATIONS  163 

aspect.  When  the  disease  is  already  well  advanced 
and  there  is  acidosis,  even  though  the  latter  may  be 
slight,  then  any  infection  becomes  a  grave  danger. 
Because  of  the  loss  of  appetite  and  fever  the  patient 
loses  weight  rapidly.  Even  when  there  is  reserve 
enough  to  combat  the  infection  the  danger  of  coma 
besets  the  convalescent.  These  considerations  apply 
to  all  of  the  severe  cases  of  diabetes  but  the  relations 
are  closest  when  the  patient  is  young. 

In  proportion  as  the  patient  is  older  the  course  of 
the  disease  tends  to  be  less  rapid  and  the  acidosis  less 
of  a  menace.  While  there  are  exceptional  cases  even  in 
advanced  life  that  progress  rapidly  to  fatal  coma,  the 
first  statement  represents  the  consensus  of  experience. 
Even  with  severe  diabetes  in  adults  the  period  of  life 
that  may  be  expected  is  longer  than  when  the  disease 
develops  during  adolescence.  On  account  of  their  im- 
poverished nutrition  these  patients  are  specially  prone 
to  serious  infections.  The  hospital  patients  with 
severe  or  moderately  severe  diabetes  usually  present 
evidence  of  pulmonary  lesions  if  the  primary  disease 
has  been  of  any  duration.  On  the  other  hand,  in  pri- 
vate practice  I  have  seen  but  four  cases  with  complicat- 
ing tuberculosis — an  exceptionally  small  percentage  I 
imagine.  The  two  diseases  may  advance  with  fearful 
rapidity  to  a  fatal  termination.  Pneumonia  claims 
many  cases  of  diabetes  either  directly  or  through  se- 


164  DIABETES  MELLITUS 

quelle.  It  is  a  common  end  with  the  milder  forms  of 
the  disease. 

A  few  cases  of  severe  diabetes  develop  a  true 
parenchymatous  nephritis,  and  in  one  instance  at  least, 
I  have  been  convinced  that  the  terminal  coma  was 
uraemic  and  not  diabetic.  It  is  possible  that  this  ter- 
mination is  less  rare  than  is  generally  supposed;  con- 
vulsions at  any  rate  should  always  excite  suspicion. 

In  striking  contrast  with  these  rapidly  developing, 
and  one  might  say,  malignant  types  of  diabetes  is  the 
manifestation  of  the  disorder  in  individuals  past  the 
meridian  of  life.  It  does  happen  that  in  advanced 
years  diabetes  may  be  of  a  severe  type ;  but  this  is  the 
exception.  Almost  every  physician  knows  of  a  man 
who  has  had  constantly  in  his  urine  for  years  one  or 
two  per  cent,  of  sugar,  whose  diet  has  been  a  mere 
farce  and  yet  fair  health  and  activity  have  been  pre- 
served. A  few  of  these  doubtless  live  to  be  sixty  or 
sixty-five  years  of  age  and  never  know  any  of  the 
serious  complications  of  their  disorder.  Some  annoy- 
ance from  polyuria,  a  little  eczema  are  the  extent  of 
their  troubles.  A  woman  whom  I  saw  in  her  later  life 
had  had  a  constant  glycosuria  for  over  fifteen  years, 
and  not  till  she  was  past  seventy  did  there  appear  any 
serious  complication,  in  this  instance  cataract,  for 
which  the  diabetes  could  be  assigned  as  a  cause. 
She  had  consulted  many  physicians  and  usually  ate 


DIAGNOSIS  AND  CONSIDERATIONS  165 

candy  ("just  one  piece")  with  after  dinner  coffee! 
Another  similar  case  was  that  of  a  man  fifty-eight 
years  old  who  was  sent  to  me  on  account  of  perforat- 
ing ulcer  in  the  foot.  He  said  he  had  been  refused 
life  insurance  when  he  was  about  forty  on  account  of 
glycosuria.  His  dietetic  restriction  had  consisted  in 
using  gluten  bread  instead  of  white  bread.  He  frankly 
confessed  no  confidence  in  diet  other  than  a  liberal  one 
and  demanded,  like  Moliere's  hero,  a  pill.  He  was  thin 
but  hale  and  had  no  significant  symptom  other  than 
the  one  mentioned. 

These  cases,  however,  cannot  be  regarded  as  the 
average  nor  is  it  ever  safe  even  in  advanced  life  to  be- 
little a  real  diabetes.  The  majority  do  not  escape 
penalties  when  they  disregard  their  disorder,  and  the 
prognosis  with  those  in  the  earlier  years  of  the  disease 
depends  not  only  on  how  easily  the  glycosuria  re- 
sponds to  curtailment  in  diet  but  also  on  the  ability  of 
the  patient  to  control  himself  and  his  surroundings. 
With  poor  patients  where  dietetic  demands  cannot  be 
met,  where  the  occupations  expose  them  more  or  less 
to  minor  injuries  which  easily  become  infected,  and 
with  whom  sanitary  surroundings  are  not  the  rule  the 
prognosis  is  much  worse  than  in  the  case  of  the  well- 
to-do.  The  complications  are  more  to  be  feared  than 
the  disease.  Of  diabetic  patients  over  fifty  years  of 
age  who  were  treated  in  the  wards  or  clinic  of  New 


166  DIABETES  MELLITUS 

York  Hospital,  I  found  that  two  deaths  occurred 
from  surgical  complications  to  every  one  in  the  medi- 
cal wards.  The  surgical  diseases  were  infections  either 
primary  or  secondary  to  some  injury. 

A  sequence  of  events  which  has  come  to  my  atten- 
tion repeatedly  in  cases  of  long  standing  is  associated 
with  the  disappearance  of  sugar  from  the  urine.  The 
explanation  assigned  for  this  disappearance  of  sugar 
is  that  there  is  a  secondary  nephritis  on  account  of 
which  the  kidney  becomes  less  permeable  to  glucose. 
In  support  of  this  conception  is  the  sequence  above 
referred  to — a  diabetes  of  mild  type  which,  having  ex- 
isted for  years,  has  first  become  intermittent  and  finally 
vanished  so  that  with  a  normal  diet  no  sugar  is  ex- 
creted. Even  before  the  sugar  is  gone  there  is  some 
increase  in  the  blood-pressure,  170  to  180  mm.  mer- 
cury, and  not  infrequently  vague  cardiovascular 
symptoms.  These  patients  are  also  prone  to  neuritis. 
The  disease  picture  from  this  time  on  is  that  of  chronic 
nephritis  and  arterial  sclerosis.  Of  four  such  cases 
(three  men  and  one  woman)  one  died  of  cerebral 
hemorrhage,  one  of  uraemia,  and  two  of  cardiac  dilata- 
tion—  in  all  four  the  modes  of  death  were  those  of  hy- 
pertensive nephritis.  In  one  of  these  cases  I  examined 
the  blood  for  glucose  and  found  0.19  per  cent.,  which 
throws  no  light  on  the  diabetic  condition,  as  increased 


DIAGNOSIS  AND  CONSIDERATIONS  167 

blood  sugar  is  not  infrequently  found  with  renal  dis- 
ease where  there  is  no  history  of  diabetes. 

Diabetes  in  middle  life  is  almost  invariably  at- 
tended by  a  demonstrable  hardening  of  the  arteries 
which  is  directly  responsible  for  many  symptoms. 
Among  the  serious  consequences  of  this  arterial  change 
is  peripheral  gangrene,  commonly  of  the  toes  or  foot, 
rarely  of  the  fingers.  This  necrosis  very  often  com- 
mences in  a  trifling  abrasion  or  bruise  which  becomes 
infected  and  by  extension  involves  the  structures  and 
periosteum,  until  there  is  a  large  area  of  dead  and 
sloughing  tissue.  The  condition  is  always  very  serious 
and  surgical  measures  disappointing.  It  too  often 
happens  that  a  low  amputation  is  followed  not  by 
healing,  but  by  a  new  area  of  necrosis,  requiring  a 
second  higher  amputation  and  so  on  until  the  ex- 
hausted patient  succumbs.  Surgical  treatment  is 
almost  hopeless  unless  it  is  accompanied  by  intelligent 
control  of  the  diet  and  often  the  latter  will  obviate  the 
need  of  radical  measures.1 

The  course  and  hence  the  prognosis  of  many  of  the 
surgical  complications  that  arise  with  diabetes  depend 
in  a  large  measure  upon  the  success  in  treating  the 
diabetes.  It  is  true  of  carbuncles  and  phlegmonous 
conditions  generally  that  after  the  necessary  opera- 
tion the  wound  is  sluggish  and  reparative  processes 

1  Lambert  and  Foster:  Annals  of  Surgery,  Feb.,  1914. 


168  DIABETES  MELLITUS 

abeyant  until  attention  is  directed  to  the  dietetic  treat- 
ment.  The  results  are  then  sometimes  astonishing  in 
the  rapidity  of  convalescence.  When  the  patient  is 
old  or  much  undermined  by  the  primary  disease  these 
infectious  processes  are  terminal. 

With  regard  to  those  glycosurias  that  accompany 
gout,  "  gouty  diabetes,"  the  vast  majority  are  not  dia- 
betes at  all,  since  the  sugar  excretion  is  not  constant. 
The  typical  glycosuria  of  gouty  subjects  is  ali- 
mentary; sugar  can  be  detected  in  the  urine  voided  a 
few  hours  after  dinner  and  not  at  other  times  during 
the  day.  Moreover,  the  glycosuria  vanishes  as  soon  as 
the  total  food  quantity  is  reduced  to  proper  amounts. 
The  condition  has  come  to  my  attention  repeatedly  in 
large  robust  individuals  who  are  heavy  feeders  and 
have  experienced  one  or  more  attacks  of  typical  gout. 
In  a  small  percentage  of  diabetics,  according  to  von 
Xoorden,  3  per  cent.,  there  is  complicating  gout.  Un- 
less the  former  disease  is  of  a  severe  type  the  prog- 
nosis depends  essentially  on  the  gouty  factors — ne- 
phritis and  arteriosclerosis. 

In  conclusion  then  the  factors  which  are  of  chief 
moment  in  determining  the  prognosis  are:  (1)  The 
age  of  the  patient.  In  youth  all  that  may  be  expected 
is  to  prolong  life  somewhat.  With  adults  and  in 
middle  life  treatment  may  hold  the  disorder  in  check 
for  indefinite  periods.     (2)  The  type  of  diabetes ;  the 


DIAGNOSIS  AND  CONSIDERATIONS  169 

outlook  is  improved  just  in  proportion  as  the  tolerance 
for  carbohydrates  can  be  increased.  (3)  With  cases 
where  there  is  a  low  tolerance  for  carbohydrates  and 
where  treatment  fails  in  establishing  an  improvement 
in  the  tolerance,  acidosis  is  sure  to  appear.  The  degree 
of  acidosis  governs  the  term  of  life  for  the  patient. 
(4)  The  social  status  controls  in  a  large  measure  the 
consideration  that  the  patient  is  able  to  give  to  his 
disorder. 


12 


XII 

TOTAL  METABOLISM  IN  DIABETES 

For  the  intelligent  care  of  cases  of  diabetes  an 
understanding  of  the  metabolism  of  the  diseased  state 
is  requisite.  Not  only  is  there  found  in  this  disease  a 
loss  of  nourishment  through  the  urine  which  must  be 
compensated  for  but  the  failure  of  the  cells  to  utilize  in 
a  normal  degree  the  nutrient  substances  presented  to 
them  results  in  various  deviations  from  normal  which 
require  attention  and  insight. 

It  is  a  well-known  fact  that  the  diabetic  loses 
weight;  in  severe  cases  this  loss  over  a  period  of  time 
may  amount  to  a  considerable  fraction  of  the  body 
weight.  Even  in  brief  periods,  a  few  days,  there  is 
often  to  be  noted  with  severe  cases  a  loss  or  gain  of 
four  or  five  pounds  which  is  not  infrequently  a  source 
of  error  in  interpretation.  Slight  fluctuations  are  nor- 
mal in  health,  and  with  this  disease  these  are  much 
magnified.  The  gain  of  a  couple  of  pounds  often  ob- 
served following  a  day  or  two  of  oatmeal  diet  or  the 
administration  of  moderate  doses  of  alkalies  cannot  be 
translated  to  mean  an  increase  in  body  tissue.  It  is 
properly  a  retention  of  water.  This  phenomenon  is 
observed  chiefly  with  the  more  severe  diabetics  where 
there  is  some  acidosis.    In  exceptional  instances  the 

170 


TOTAL  METABOLISM  IN  DIABETES  171 

use  of  alkalies  may  effect  sufficient  water  retention  so 
that  palpable  oedema  is  manifested.  On  the  other 
hand,  sudden  losses  in  weight  may  be  due  solely  to 
loss  of  water.  BischofF  and  Voit  observed  a  half 
century  ago  that  with  a  diet  chiefly  composed  of  car- 
bohydrate there  is  a  retention  of  water  and  in  more  re- 
cent experiments  1  it  has  been  shown  that  when  with 
normal  men  the  carbohydrate  of  the  diet  is  largely  re- 
placed by  fat  there  resulted  an  average  loss  of  900 
grammes  of  water  per  day  for  three  days — nearly  six 
pounds.  There  is  something  in  the  nature  of  a  rich 
carbohydrate  diet  that  normally  causes  retention  of 
water  and  when  the  carbohydrate  is  replaced  by  fat 
and  protein  the  tissues  release  the  fluid.  When  with 
cases  of  diabetes  the  carbohydrate  ingest  is  sharply 
reduced  there  is  often  to  be  observed  a  loss  in  weight 
during  the  first  few  days  of  the  new  diet  which  is  ex- 
plicable entirely  as  a  loss  of  water.  Even  with  severe 
cases  this  rate  of  loss  does  not  persist  over  long 
periods.  If  it  be  borne  in  mind  that  about  60  per 
cent,  of  the  body  is  water  it  then  becomes  evident  that 
slight  fluctuations  in  the  percentage  of  water  accrue 
to  considerable  gains  or  losses  in  weight.  In  order  to 
explain  persistent  fall  in  weight  over  long  periods  of 
time  we  must  look  to  actual  tissue  loss;  and  of  the 

1  Benedict  and  Milner:   U.  S.  Dept.   Agr.  Office  Exp.   Stats.   Bui., 
175,  1907,  p.  225. 


172  DIABETES  MELLITUS 

constituents  of  the  body — protein,  fat,  and  carbohy- 
drate,— it  is  the  fat  that  largely  suffers  depletion. 
The  amount  of  carbohydrate  in  the  body  is  relatively 
small,  ordinarily  about  400  grammes  of  glycogen,  and 
the  loss  of  a  large  part  of  this  would  effect  only  a 
trivial  fall  in  weight ;  moreover,  as  the  organism  alike 
in  health  and  disease  conserves  its  protein,  it  follows 
that  tissue  loss  must  be  at  the  expense  of  fat.  When 
the  fat  depots  are  exhausted  there  may  be  an  inroad 
upon  the  more  vital  tissue,  protein. 

With  normal  man  at  rest  there  is  a  constant  de- 
mand of  energy  for  the  maintenance  of  body  tempera- 
ture, the  muscular  work  of  the  heart  and  various 
cellular  processes  such  as  digestion;  this  demand 
amounts  in  adults  to  from  30  to  32  calories  per  kilo 
body  weight  per  day.  Since  the  diabetic  organism 
fails  more  or  less  to  make  use  of  one  of  the  chief 
sources  of  energy  in  health,  sugar,  the  question  arises 
as  to  the  sources  of  the  necessary  energy  in  this  dis- 
ease. Also  the  question  must  be  answered  as  to 
whether  the  total  metabolism  is  in  amount  different  or 
the  same  as  in  health. 

Fat  and  carbohydrate  contain  the  elements  carbon, 
hydrogen,  and  oxygen  and  the  resultant  products  of 
oxidation  are  C02  and  H20.  With  protein  there  is 
the  additional  nitrogen  which  is  excreted  in  the  urine 
as  urea,  ammonia,  etc.    Hence  a  measure  of  the  total 


TOTAL  METABOLISM  IN  DIABETES  173 

tissue  metabolism  is  found  in  the  estimation  of  the  car- 
bon and  nitrogen  excretion. 

First  with  regard  to  the  nitrogen  metabolism. 
With  normal  individuals  the  nitrogen  excreted  in  the 
urine  during  periods  of  fasting  averages  about  6.8 
milligrammes  per  kilo  per  hour.  With  diabetic 
patients  this  figure  tends  to  be  higher,  according  to 
Benedict  and  Joslin,2  8.4  milligrammes  per  kilo- 
gramme per  hour  as  an  average  and  with  individual 
cases  somewhat  more.  This  increase  is  not  held  to 
be  a  specific  action  of  some  factor  in  the  morbid  state 
upon  protein  but  rather  as  one  of  the  compensatory 
measures  for  the  carbohydrate  deficit. 

There  are  several  methods  of  investigating  the 
carbon  dioxide  excretion  and  oxygen  absorption  and 
results  vary  slightly,  depending  on  whether  the 
chamber  calorimeter  is  employed  or  the  respiration 
apparatus  of  Zuntz.  In  the  absence  of  better  evi- 
dence an  average  of  the  results  obtained  by  the  two 
methods  with  the  same  diabetic  patients  may  be  cited. 
Benedict  and  Joslin  found  the  carbon  dioxide  produc- 
tion for  severe  diabetes  amounts  to  3.33  c.c.  per  kilo- 
gramme of  body  weight  per  minute;  while  with  nor- 
mal persons  it  is  3.13  c.c.  This  means  an  increase  of 
approximately  6  per  cent,  with  the  diabetic.    The  rate 

a Benedict  and  Joslin:  A  Study  of  Metabolism  in  Severe  Diabetes. 
Carnegie   Institute,  Washington,    1912,  p.   102. 


174  DIABETES  MELLITUS 

and  amount  of  oxidation  in  the  body  can  also  be 
measured  by  using  as  an  index  the  amount  of  oxygen 
absorbed.  By  some  the  oxygen  consumption  is  re- 
garded as  of  greater  significance  in  measuring  the 
caloric  output  than  is  the  carbon  dioxide  production. 
The  oxygen  consumption  with  normal  men  is  3.75  c.c. 
per  kilogramme  per  minute  and  with  severe  cases  of 
diabetes  4.54  c.c.3  Even  higher  figures  have  been 
noted  by  Roily4  and  by  Leindorfer.5  Using  these 
figures  as  an  index  Benedict  and  Joslin  conclude  that 
the  metabolism  in  severe  diabetes  is  from  15  to  20  per 
cent,  higher  than  normal.  Translated  into  terms  of 
heat  units  this  would  mean  that  whereas  the  normal 
person  at  rest  requires  about  32  calories  per  kilo  body 
weight  cases  of  severe  diabetes  utilize  37  to  38  calories. 
This  conclusion  is  not  in  harmony  with  the  results  of 
other  investigations.  It  has  been  the  belief  that  the 
energy  requirements  in  diabetes  are  about  5  per  cent, 
above  the  normal.  DuBois  and  Vedder6  found  the 
requirement  31.7  calories  per  kilo  for  mild  and  34 
calories  for  severe  cases  of  diabetes,  results  that  are  in 
accord  with  the  older  investigations.7     Benedict  and 

•Benedict   and   Joslin:   loc.   cit. 
4  Roily:  Deut.  Arch.  f.  klin.  Med.,  1912,  105,  p.  494. 
"Leindorfer:  Biochem.  Zetschr.,  1912,  40,  p.  326. 
•  Arch,  for  Intern.  Med.,  1910,  v,  p.  37. 

7  Magnus-Levy :  Von  Noorden's  Handbuch  d.  Pathol,  d.  Stoffwechels, 
1906,  p.  291. 


TOTAL  METABOLISM  IN  DIABETES  175 

Joslin  believe  the  heightened  metabolism  is  connected 
with  acidosis  since  it  was  found  that  by  inducing 
acidosis  in  normal  men  with  diets  poor  in  carbohy- 
drate there  resulted  here  also  an  increase  of  carbon 
dioxide  excretion  and  oxygen  consumption. 

The  carbon  dioxide  production  and  oxygen  con- 
sumption not  only  serve  as  a  guide  to  the  amount  of 
energy  produced  but  they  may  also  be  used  to  indi- 
cate the  character  of  the  catabolic  process.  That  is  to 
say,  the  respiratory  quotient  indicates  whether  fat, 
carbohydrate,  or  protein  is  undergoing  oxidation  in 
the  tissues.  The  respiratory  quotient  is  derived  by 
dividing  the  volume  of  carbon  dioxide  produced  by  the 
volume  of  oxygen  consumed  (^2)  •  For  the  oxidation 
of  one  molecule  of  glucose  to  C02  and  H20  six  mole- 
cules of  oxygen  are  necessary,  and  there  result  six 
molecules  of  carbon  dioxide  plus  water  and  the  respira- 
tory quotient  is  then  one. 

C6Hi206+602  =  6C02+6H20 

Egg  albumen  will  serve  as  a  typical  protein  and 
derives  a  respiratory  quotient  of  0.8. 

Cio2Hi6oN26033S-f-107£02  =  89C02+54H20+13CO(NH2)2+S03 

89 
10^5  -82 


176  DIABETES  MELLITUS 

With  suitable  apparatus  it  is  possible  to  measure  the 
oxygen  consumed  and  the  carbon  dioxide  produced 
during  any  given  interval  of  time,  and  from  these  re- 
sults then  it  may  be  definitely  ascertained  whether 
either  carbohydrate,  fat,  or  protein  is  being  metab- 
olized. When  the  body  is  burning  mostly  carbohy- 
drates the  respiratory  quotient  is  near  one;  on  the 
other  hand,  when  fats  and  proteins  are  being  consumed 
the  quotient  is  something  over  0.7.  Now  in  the  first 
place  this  quotient  offers  a  means  of  detecting  whether 
the  diabetic  organism  can  burn  carbohydrate,  for  if 
the  quotient  is  not  raised  following  the  ingestion  of 
this  food  it  follows  that  the  sugar  is  not  catabolized. 
With  diabetes  it  is  found  that  the  respiratory  quotient 
is  lower  than  normal,  ranging,  according  to  different 
observers,  from  0.66  to  0.76,  and  that  the  lowest 
quotients  are  found  with  the  most  severe  cases  of  the 
disease.  Benedict  and  Joslin8  recorded  0.74  for 
severe  cases  and  0.76  for  light  cases  of  diabetes;  and 
Roily  9  noted  much  lower  results  for  severe  cases.  A 
quotient  that  is  0.74  or  lower  indicates  that  the  body 
is  consuming  chiefly  fat.  The  slight  rise  over  the  quo- 
tient for  purely  fat  combustion  of  0.71  is  due  to  the 
metabolism  of  small  amounts  of  protein;  and  a  fall 
below  this  figure  is  caused,  as  Magnus-Levy  pointed 

8  Loc.  cit.,  p.  111. 

•  Deut.  Arch.  f.  klin.  Med.,  1911,  102,  p.  494. 


TOTAL  METABOLISM  IN  DIABETES  177 

out,  by  the  incomplete  fat  combustion  manifested  in 
the  excretion  of  ketone  bodies  in  the  urine.  The  net 
result  then  of  studies  of  the  respiratory  quotient  indi- 
cates that  the  metabolism  in  severe  diabetes  is  prima- 
rily fat  metabolism  in  contrast  to  normal,  which  is 
primarily  one  of  carbohydrate. 

There  is  not  a  sufficiency  of  data  bearing  on  the 
influence  of  muscular  work  upon  the  quotient  in 
severe  diabetes  to  give  basis  for  definite  conclusions. 
With  some  cases  the  quotient  is  lowered  indicating 
perhaps  a  relative  increase  of  fat  over  the  protein 
factor  in  catabolism.  With  other  cases  there  has  been 
observed  a  rise  in  the  quotient  which  might  be  inter- 
preted to  mean  a  combustion  of  stored  carbohydrate 
(glycogen) .  That  the  severe  diabetic  can  burn  small 
amounts  of  reserve  glycogen  under  stress  of  work  is 
possible  and  the  idea  has  been  advanced  as  an  explana- 
tion for  the  increased  acid  production  that  some  cases 
manifest  following  exertion.  This  explanation  is 
based  on  the  assumption  that  the  glycogen  stores  in- 
hibit acidosis;  as  these  stores  are  depleted  acidosis  in- 
creases. If  this  be  correct  the  acidosis  following  acute 
infections  in  diabetic  subjects  can  be  explained  on  the 
same  basis,  the  glycogen  stores  are  exhausted  during 
the  febrile  period. 

Thus  far  then  it  appears  from  a  study  of  the 


178  DIABETES  MELLITUS 

metabolism  that  in  proportion  to  the  severity  of  the 
disease  there  is  a  decrease  in  the  ability  of  the  tissues 
to  utilize  sugar.  Sugar  normally  saves  protein  and 
fat  to  the  body  by  being  given  preference  as  fuel  in 
the  tissues,  or,  as  it  is  commonly  expressed,  sugar  is  a 
protein  sparer.  When  the  sugar  is  not  utilized  there  is 
increased  catabolism  of  protein  and  fat  and  this  is  evi- 
denced in  the  respiratory  quotient  and  the  nitrogen 
excretion. 

The  sugar  of  the  body  is  derived  from  two  sources : 
from  carbohydrates,  ingested  or  stored  as  glycogen; 
and  from  protein,  either  of  food  or  tissues.  In  severe 
diabetes  the  sugar  derived  from  protein  is  also  ex- 
creted unburned ;  hence  it  may  be  possible  to  estimate 
in  some  cases  the  severity  of  the  diabetes  from  the 
dextrose-nitrogen  in  the  urine.  As  noted  already  this 
ratio  is  a  nearly  constant  quantity  in  dogs  after  total 
removal  of  the  pancreas  and  after  phlorhizin.  With 
a  diabetic  man  Mandel  and  Lusk 10  secured  a  dextrose- 
nitrogen  ratio  of  3.6  which  would  indicate  that  all  of 
the  sugar  derived  from  protein  was  being  excreted  in 
the  urine  and  none  burned  and  hence  this  ratio  was 
called  the  fatal  ratio.  Since  this  observation  a  number 
of  investigators  have  reported  cases  of  diabetes  where 
the  ratio  was  much  higher  than  3.6  to  1  and  have 

10  Deutsches  Arch.  f.  klin.  Med.,  1904,  81,  p.  472. 


TOTAL  METABOLISM  IN  DIABETES  179 

endeavored  to  prove  from  this  that  sugar  must  be 
derived  from  fat  as  well  as  protein.  The  error  com- 
mon in  these  experiments  has  been  that  the  diet  was 
not  sufficiently  controlled.  While  it  is  theoretically 
possible  that  sugar  may  be  derived  from  fatty  acids 
the  fact  is  wholly  undemonstrated.  Using  as  a  sub- 
ject for  experiment  a  man  with  the  severest  type  of 
diabetes  and  with  coma  symptoms  requiring  infusions 
of  alkali  Foster  ir  found  a  ratio  of  3.4-3.6  for  3  days 
during  which  the  diet  was  exclusively  meat  and  fat. 

From  the  point  of  view  of  available  energy  the 
diabetic  might  live  indefinitely  on  a  diet  of  meat  and 
fat.  The  condition  is  purely  that  of  substituting  one 
energy  yielding  substance  for  another.  With  severe 
diabetes,  however,  there  comes  a  time  when  fats  are 
but  incompletely  utilized  and  this  is  marked  by  the 
excretion  of  the  partly  catabolized  products,  the 
ketone  bodies,  in  the  urine.  This  may  be  no  incon- 
siderable drain  upon  the  struggling  organism  as  each 
gramme  of  £-oxybutyric  acid  means  a  loss  of  4.4 
calories,  that  is  an  excretion  of  50  grammes  of  oxy- 
butyric  acid  represents  220  calories.  In  the  condition 
of  total  diabetes  where  the  sugar  derived  from  protein 
is  not  burned  the  ruinous  economic  state  is  revealed 
clearly  in  figures.     If  there  be  an  excretion  of  15 

"Foster:  Deut.  Arch.  f.  klin.  Med.,  1913,  no,  p.  501. 


180  DIABETES  MELLITUS 

grammes  of  nitrogen  in  the  urine  this  represents  94 
grammes  of  catabolized  protein  (15  X  6.25) ;  the  heat 
value  of  which  is  374  calories.  From  this  protein  then 
is  derived  54  grammes  of  sugar  (15  X3.6)  equal  to 
221  calories  or  58  per  cent,  of  the  total  heat  value  lost. 
If  in  addition  the  butyric  acid  derived  from  the  amino- 
acids  is  not  burned  but  excreted  in  the  urine  the  loss  is 
even  more. 


XIII 

TREATMENT 

In  the  majority  of  cases  the  presence  of  sugar  in 
the  urine  is  attended  by  so  few  urgent  symptoms 
threatening  life,  or  even  efficiency,  that  physicians  too 
often  are  content  with  the  slightest  attempts  to  restore 
a  more  normal  condition.  For  example,  it  has  re- 
quired considerable  reiteration  to  awaken  a  realization 
that  the  percentage  of  sugar  in  a  single  specimen  of 
urine  really  gives  no  indication  whatever  concerning 
the  patient's  disease.  A  low  percentage  has  been  re- 
garded as  negligible  and  only  with  the  advent  of  com- 
plications is  there  an  effort  made  toward  treatment. 
It  has  become  an  old  story  on  seeing  cases  in  coma  to 
be  informed  that  the  sugar  had  never  been  over  two 
per  cent.  A  complete  twenty-four  hour  specimen  later 
sometimes  measures  over  five  litres  and  discloses  a  new 
significance  to  percentage.  While  it  is  doubtless  true 
that  some  cases  of  diabetes  that  develop  in  later  life 
run  a  mild  course  and  live  out  the  allotted  three  score 
and  ten,  yet  we  are  at  present  unable  to  differentiate 
these  individuals  from  the  less  fortunate  ones  who 
suffer  from  numerous  complications.  Now  since  it 
has  been  repeatedly  shown  that  of  the  latter  class  the 

181 


182  DIABETES  MELLITUS 

majority  can  be  rid  of  the  distressing  and  dangerous 
elements  in  their  disorder  by  suitable  treatment,  then 
it  seems  more  than  probable  that  had  proper  care  been 
exercised  the  complications  would  not  have  arisen. 

A  small  percentage  of  the  cases  of  diabetes  may  be 
separated  from  the  whole  on  account  of  the  promi- 
nence of  some  specific  disorder  in  the  clinical  picture 
requiring  special  treatment  and  this  disorder  generally 
relates  to  the  gastro-intestinal  tract.  Dietrich  found 
a  catarrhal  gastritis  in  67  per  cent,  of  his  cases.  Oc- 
casionally treatment  directed  to  the  gastritis  is  bene- 
ficial also  to  the  diabetic  condition.  A  number  of 
such  cases  have  been  reported  by  Funk  *  where  the 
treatment  of  achylia  gastrica,  or  colitis  has  apparently 
raised  the  sugar  tolerance  of  the  patient  to  a  very 
large  degree.  I  have  also  met  with  instances  of  well 
marked  gastritis  but  I  have  not  been  fortunate  in  pro- 
ducing any  essential  change  in  the  diabetic  state  by 
gastric  lavage  as  advised  by  Dietrich  and  others.  It 
has  even  been  claimed  that  with  some  cases  so  treated 
the  sugar  disappears  from  the  urine  even  on  a  nor- 
mal diet,  that  is,  the  patient  is  actually  cured.  With 
suitable  cases  the  procedure  is  worthy  of  trial  since 
for  no  other  measure  at  our  command  can  a  like  claim 
be  substantiated. 

There  have  been  reported  several  cases  where  the 

1  Medizinisch.  Klinik.,  1912,  vm,  No.  33. 


TREATMENT  183 

sugar  has  disappeared  from  the  urine  following  the 
removal  of  a  tumor — hysterectomy  for  carcinoma, 
prostatectomy  on  account  of  hypertrophy.  These  in- 
stances are  excessively  rare  and  we  have  no  explana- 
tion for  the  phenomena  mentioned.  For  the  vast 
majority  of  cases  the  only  therapeutic  agent  that 
yields  any  degree  of  success  is  diet. 

The  problem  presented  in  each  diabetic  individual 
is:  How  much  sugar  can  he  utilize?  The  answer  to 
this  question  is  important  since  if  a  surplus  over  the 
amount  which  can  be  cared  for  by  the  tissues  be  in- 
gested, not  only  is  that  excess  excreted  but  the  ability 
of  the  tissues  to  use  sugar  is  gradually  diminished ;  or 
as  Hoffman  stated  the  principle  for  all  physiological 
activities : — Overstrain  weakens  while  rest  strengthens 
any  damaged  function.  In  diabetes  we  have  to  do 
with  an  impaired  function,  the  tissues  are  not  able  to 
make  use  of  sugar  as  a  source  of  energy,  nor  can  sugar 
be  warehoused  as  glycogen.  These  functions  are  com- 
pletely lost  only  in  the  terminal  stages  of  the  very 
severe  cases,  in  all,  however,  they  are  in  some  degree 
below  normal.  Dietetic  treatment  has  for  its  object 
the  regulation  of  the  demand  made  upon  this  function 
so  that  there  may  be  opportunity  for  recuperation,  i.e., 
an  increased  ability  to  metabolize  carbohydrate.  This 
is  the  governing  principle  and  all  methods,  no  matter 


184  DIABETES  MELLITUS 

on  what  theory  of  etiology  nor  how  devious,  are  efforts 
to  this  end. 

Since  the  demands  made  upon  the  body  to  use  car- 
bohydrate are  to  be  limited  to  its  capacity  it  follows 
that  some  method  must  be  employed  in  the  first  in- 
stance to  test  this  function  in  each  case  presented.  In 
order  to  do  this  a  standard  diet  of  known  composition 
is  given  the  patient,  then  the  urine  analyses  enable 
the  observer  to  estimate  with  some  degree  of  exactness 
the  amount  of  carbohydrate  actually  metabolized  by 
this  patient.  Because  it  is  not  advisable  to  eliminate 
at  once  all  of  the  carbohydrate  from  the  diet  it  is 
customary  to  incorporate  in  this  test  diet  a  small 
known  amount  of  starch.  For  convenience  it  is 
advisable  to  use  a  starch  preparation  that  is  fairly 
constant  in  composition  and  since  breads  are  very 
inconstant  a  standard  biscuit  is  preferable.  The  fol- 
lowing diet  has  been  found  satisfactory  although  it 
has  nothing  of  special  merit  other  than  that  the  com- 
position is  known  approximately. 

"TEST"   DIET 
Breakfast: 

3  eggs  with  25  gm.  of  bacon. 

3  biscuits    (Huntley   and   Palmer    "Breakfast")2   with   20    gm.   of 
butter. 

1  cup  of  strong  coffee  with  25  c.c.  of  cream. 

2  The  biscuits  have  been  analyzed  at  intervals  in  my  laboratory  and 
found  approximately  constant  in  starch  content.  Each  biscuit  contains 
from  4.87  to  5.13  grammes  carbohydrate. 


TREATMENT  185 

Dinner: 

1  cup  of  bouillon. 

150  gm.  of  beefsteak  or  roast  beef   (weighed  cooked). 

Boiled  cabbage  or  cauliflower  with  butter  sauce  ad  libitum;  lettuce 
with  oil  and  vinegar. 
4  to  5  p.m.: 

Coffee  or  tea  with  25  gm.  of  cream. 

1  biscuit,  10  gm.  of  butter. 
Slipper : 

100  gm.  of  fish  (weighed  cooked). 

2  eggs. 

Asparagus  as  salad  or  hot  (with  butter  sauce). 

3  biscuits ;  20  gm.  of  butter. 
1   dozen  almonds. 

This  "test"  diet  contains  from  50  to  55  grammes  of 
carbohydrate  (estimated  as  glucose)  and  about  16 
grammes  of  nitrogen  (16  x  6.25  =  100  grammes  pro- 
tein) .  It  is  necessary  to  use  a  "  test  "  diet  for  at  least 
two  days  as  there  is,  during  the  first  twenty-four 
hours,  an  excretion  of  sugar  representing  that  formed 
from  the  food  consumed  before  the  diet  is  begun.3 
The  twenty-four  hour  collection  of  urine  for  the 
second  day  of  the  test  diet  must  be  examined  with 
care  in  order  to  learn  the  facts  which  determine  the 
future  treatment  of  the  case.  In  addition  to  quantita- 
tive estimation  of  the  glucose  the  urine  must  be  tested 
for  diacetic  acid  and  if  the  latter  be  present  the  total 
ammonia  should  be  estimated  as  a  guide  to  the  degree 
of  acidosis.    The  determination  of  the  total  nitrogen 

3  The  total  carbohydrate  value  of  the  diet  should  include  the  glucose 
available  from  the  protein.  This  latter  would  amount  to  58  gm.  (16  X  3.6 
=  57.6),  hence  the  total  available  glucose  is  108  gm.  (58  +  50). 

13 


186  DIABETES  MELLITUS 

is  advisable  since  it  enables  one  to  form  a  more  accu- 
rate estimate  of  the  severity  of  the  diabetes  as  will  be 
seen.  It  is  customary  to  classify  cases  of  diabetes 
somewhat  crudely  into  mild  and  severe  types  of  the 
disease;  and  these  terms  take  into  account  the  whole 
clinical  picture  as  well  as  the  result  of  analyses  of 
the  urine  after  standard  diets.  It  is  apparent  that 
the  degree  of  severity  of  the  disease  depends  upon  the 
ability  preserved  to  utilize  sugar  in  the  body.  This 
point  may  be  illustrated  by  examples :  if  a  diabetic  in- 
dividual be  given  the  "test"  diet  and  excrete  30 
grammes  of  sugar  then  it  is  evident  that  he  retains  the 
function  of  utilizing  some  sugar,  in  this  instance  78 
grammes.  He  has  metabolized  some  20  grammes  of 
sugar  from  starch  ( since  the  diet  contains  50  grammes 
of  carbohydrate  in  that  form)  and  all  the  glucose  from 
protein,  58  grammes.  On  the  other  hand,  if  the  urine 
under  the  same  diet  restriction  contain  80  grammes  of 
sugar  then  we  may  conclude  no  sugar  from  starch  has 
been  metabolized  and  of  that  derived  from  protein  only 
38  grammes  have  been  retained  to  the  body.  These 
examples  mark  a  distinguishing  feature  in  differentia- 
tion of  the  disease ;  in  the  first,  carbohydrates  are  still 
utilized  though  in  a  restricted  degree,  in  the  second  the 
body  fails  not  only  to  metabolize  sugar  from  starch 
but  also  fails  to  retain  a  part  of  the  glucose  from  pro- 


TREATMENT  187 

tein.    The  first  condition  would  represent  a  mild  dia- 
betes and  the  second  one  of  moderate  severity. 

Lusk  and  Falta  have  suggested  a  means  of  more 
accurate  expression  of  the  various  grades  of  diabetes, 
by  a  quotient,  and  at  the  same  time  bridging  the  diffi- 
culties of  comparison  of  various  cases  treated  with 
different  diets.    This  quotient  is : 

Grammes  of  urinary  sugar  X  100 


Grammes  of  N  X  3.65+ grammes  sugar  ingested 
30X100 


14X3.65+50 

80X100 
15.5X3.65+50! 


=  29 


75 


Applying  this  formula  to  the  first  case  cited  the  quo- 
tient is  29  and  in  the  second  case  75.  Total  diabetes 
wherein  no  sugar  at  all  is  metabolized  would  present 
a  quotient  of  100.  For  the  employment  of  this 
formula  it  is  necessary  to  know  the  total  nitrogen  of 
the  urine.  The  advantage  in  its  use  is  that  an  index 
is  obtained  which  is  more  definite  than  the  vague 
terms  mild  and  severe. 

The  results  of  the  analysis  of  urine  after  the  use 
of  the  test  diet  enable  us  to  classify  cases  for  therapeu- 
tic measures.  The  analysis  will  fall  into  one  of  the  fol- 
lowing divisions. 


188  DIABETES  MELLITUS 

1.  Sugar  less  than  50  grammes;  ketone  bodies 
absent. 

2.  Sugar  more  than  50  grammes;  ketone  bodies 
absent. 

3.  Sugar  more  than  50  grammes;  ketone  bodies 
present. 

The  first  classification  embraces  the  milder  grades 
of  the  disorder  where  some  carbohydrate  is  still  metab- 
olized in  the  body  and  where  there  is  no  acidosis.  The 
following  history  is  that  of  a  case  of  this  type. 

Mr.  W.  R.,  Savannah;  age  forty-nine.  Patient  had 
a  brother  who  died  of  diabetes,  but  no  other  member  of 
the  family  has  been  affected.  He  has  always  been  well 
and  healthy  until  about  a  year  ago  and  has  always 
worked  under  heavy  responsibilities.  He  has  been  a 
large  eater  and  a  moderate  user  of  alcohol.  About  a 
year  ago  he  felt  "  run  down  "  and  tired  and  noted  that 
he  was  losing  weight,  and  somewhat  later  thirst  be- 
came excessive  and  he  voided  considerable  urine. 
Suspecting  Bright's  disease  a  physician  was  consulted 
and  sugar  found  in  the  urine.  In  consequence  of  ab- 
staining from  sugar  and  sweets  the  patient  thinks  he 
has  improved.  He  is  a  well  built  man  weighing  153 
pounds,  and  presenting  nothing  abnormal  in  his  ex- 
amination other  than  a  palpable  liver  which  extends  2 
inches  below  the  costal  margin  in  the  mid-clavicular 


TREATMENT 


189 


line  and  does  not  feel  rough  nor  unduly  hard.  The 
urine  contained  sugar,  but  no  albumen ;  specific  gravity 
1032.  The  urine  of  the  third  day  of  the  "test"  diet  is 
the  first  analysis  of  the  table. 


1911 

Amount. 

Sugar. 

Nitrogen. 

Ketone. 

May 

Diet. 

c.c. 

Albumen. 

gm. 

gm. 

gm. 

10 

Test 

1210 

0 

1.2 

per  cent. 

=  14.5 

17.3 

0 

11 

Test 

1230 

0 

0.3 

per  cent. 

=  3.7 

15.4 

0 

12 

C.F* 

1220 

0 

trace 

16.1 

0 

13 

C.F 

1460 

0 

0 

. . . 

0 

14 

C.F 

1440 

0 

0 

. . 

0 

15 

50  gm.  bread. 

1035 

0 

0 

. . 

0 

16 

C.F 

1620 

0 

0 

. . 

0 

17 

60  gm.  bread. 

1630 

0 

0 

. . 

0 

18 

C.F 

960 

0 

0 

. . 

0 

19 

60  gm.  bread . 

1050 

0 

0 

. . 

0 

20 

60  gm.  bread . 

1190 

0 

0 

. . . 

0 

21 

C.F 

1080 

0 

0 

0 

June 

1 

90  gm.  bread . 

1370 

0 

0 

0 

•"  C.  F."  in  these  tables  signifies  carbohydrate-free  diet. 

The  notable  features  presented  by  this  case  are: 
the  slight  sugar  excretion  even  while  the  diet  contained 
starch;  the  prompt  disappearance  of  sugar  from  the 
urine  when  the  starch  was  withheld ;  and  the  rapid  in- 
crease of  the  tolerance  of  the  patient  so  that  within 
three  weeks  80  to  90  grammes  of  bread  could  be  taken 
without  glycosuria.  By  gradual  increments  the  diet 
was  further  enlarged  until  this  patient  was  ingesting 
the  equivalent  of  110  grammes  of  carbohydrate  in 
various  foods.  The  principle  to  be  observed  in  enlarg- 
ing the  diet  is  that  additions  must  be  made  gradually 
in  small  increments,  keeping  all  the  time  well  within 


190  DIABETES  MELLITUS 

the  bounds  of  the  patient's  tolerance ;  and  second,  the 
interpolation,  at  definite  intervals,  of  strict  diet  days 
when  no  starch  is  taken.  These  days  may  be  observed 
once  a  week  or  every  tenth  day  and  are  no  hardship  to 
the  patient.  In  this  way  cases  of  mild  diabetes  may  be 
kept  without  glycosuria  for  very  long  periods  and  in 
excellent  health.4  With  many  the  disease  appears  to 
have  no  progressive  tendency.  This  patient  has  been 
under  observation  at  intervals  for  three  years  and 
while  it  has  not  been  possible  to  increase  his  allowance 
of  farinaceous  food  there  has  been  no  appreciable 
failure  in  his  ability  to  utilize  the  amount  permitted 
at  the  end  of  his  first  treatment. 

A  great  many  cases  that  assume  a  severe  char- 
acter with  the  lapse  of  time  are  in  the  early  stages  of 
this  bland  nature.  With  some  the  disease  does  not 
progress ;  with  others  it  does  and  I  know  of  no  way  of 

4  Diabetes  of  even  milder  grades  is  of  common  occurrence.  These 
patients  are  generally  huge  feeders  who  have  presumed  upon  ex- 
cellent stomachs  to  indulge  unbridled  appetites.  The  glycosuria  is  of 
slight  degree,  with  little  if  any  polyuria,  and  vanishes  as  soon  as  the 
total  food  quantity  is  made  normal.  These  are  the  cases  where  the  various 
advertised  medicaments  produce  their  results  and  purely  by  means  of 
the  slight  diet  regulations  that  are  advised.  If  one  case  of  this  type, 
a  man  of  forty-eight  years  of  age,  ate  what  he  said,  the  carbohydrate 
ingest  was  not  less  than  800  grammes  per  day  and,  as  his  urinary 
nitrogen  was  over  30  grammes,  the  protein  allowance  was  equally  liberal. 
Allowing  for  a  normal  amount  of  fat  the  caloric  value  of  this  diet  was 
about  4500  or  some  50  calories  per  kilo  to  supply  the  needs  of  a  sedentary 
mode  of  life.  His  glycosuria  vanished  without  restrictions  worthy  of  the 
name. 


TREATMENT  191 

differentiating  in  the  beginning  the  mild  cases  from 
the  early  manifestations  of  more  severe  disease  types. 
The  following  record  illustrates  a  transition  and  im- 
provement with  time. 

G.  S.,  Pittsburg,  Pa.,  aged  thirty-four.  He  came 
from  a  healthy  family  and  had  had  no  significant 
sickness  before  the  onset  of  diabetes.  He  had  alwavs 
been  a  large  eater  and  particularly  fond  of  sweets. 
In  August,  1911,  on  account  of  some  slight  digestive 
disturbance  he  consulted  his  physician  who  found 
sugar  in  the  urine.  Abstinence  from  sugar  and  some 
starch  reductions  in  the  diet  resulted  in  the  glycosuria 
disappearing  promptly.  Urine  analyses  were  made 
at  least  once  a  week  and  no  sugar  was  found  until 
December,  1911.  At  this  time  the  common  dietary 
restrictions  failed  and  the  glycosuria  persisted  and  the 
patient  began  for  the  first  time  to  have  some  increase 
in  the  amount  of  urine  voided.  Also  his  weight  fell 
from  180  to  170  pounds. 

The  patient  began  treatment  March  4,  1912. 
With  the  diet  he  was  using  the  amount  of  urine  varied 
from  2700  to  3400  c.c.  daily,  containing  60  to  70 
grammes  of  glucose.  On  the  third  day  of  the  test  diet 
the  sugar  fell  to  6.7  grammes  and  the  results  of  the 
first  course  of  treatment  are  shown  in  the  table. 


192  DIABETES  MELLITUS 

Date.  Amount 

1912  urine.  Sugar.         Nitrogen.        Ketone. 

March  Diet.  ex.  gm.  gm.  gm. 

9  Test 1920  6.70           16.8              0 

10  Oatmeal 1500  7.5 

11  C.  F 800  2.1 

12  C.  F 1300             0 

13  50  gm.  carbohydrate 1500  7.1 

14  C.  F 1100      0 

15  C.  F 1230      0 

16  C.  F 1180     0 

17  20  gm.  carbohydrate 1210      0 

18  C.  F 1070     0 

19  C.  F 1150     0 

20  30  gm.  carbohydrate 1320     0 

21  C.  F 1700     0 

22  50  gm.  carbohydrate 1250     0 

23  50  gm.  baked  potato 1610     0 

24  50  gm.  bread 1750     0 

25  C.  F 1730     0 

26  125  gm.  potato 1700             0 

27  100  gm.  bread  and  potato.  1670  trace 

The  record  of  this  case  indicates  an  easily  con- 
trolled glycosuria.  His  test  March  9,  1912,  showed 
that  he  still  utilized  about  40  grammes  of  ingested 
starch  and  the  total  sugar  consumption  was  about  90 
grammes.  There  was  at  no  time  any  evidence  of 
acidosis.  During  the  period  of  treatment  his  weight 
rose  from  164  to  170  pounds.  He  was  sent  home 
with  directions  to  use  not  more  than  50  grammes 
of  carbohydrate  a  day,  and  not  more  than  two  starch- 
containing  foods  in  the  same  day;  every  fourth  day 
to  be  restricted  and  starch  free.  He  felt  himself  to 
be  in  normal  health  and  the  urine  contained  sugar 
only  at  intervals  until  June,  1913.  There  was  then 
some  relaxation  in  the  care  he  had  shown  heretofore 
in   following   directions   and   sugar  was   constantly 


TREATMENT  193 

present  although  in  but  small  amounts.    The  second 
period  of  treatment  began  in  October,  1913. 

Date.  Amount 

1913  urine. 

October  Diet.  c.c. 

24  Test 1160 

25  C.  F 1080 

26  30  gm.  carbohydrate 1270 

27  C.  F 1250 

28  30  gm.  carbohydrate 1320 

29  30  gm.  potato 1290 

30  C.  F 1060 

November 

1  C.  F 990 

2  75  gm.  carbohydrate 

(potato  and  bread) 1370 

3  C.  F 1100 


Sugar. 

Nitrogen. 

Ketone. 

gm. 

gm. 

£7771. 

4.6 

15.31 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

7.2 

14.2 

0 

trace 

0 

The  result  of  the  third  day  of  the  test  period 
showed  that  this  patient  was  consuming  about  100 
grammes  of  sugar,  of  which  45  grammes  was  derived 
from  starch  and  about  55  grammes  from  protein 
(15.31N  X  3.6  =  55.08  grammes)  and  this  was  in- 
creased to  over  115  grammes  on  November  second 
(14.2  X  3.6  =  51  +  75  =  126  —  7  =  119) .  No  at- 
tempt was  made  at  this  time  to  arrive  at  a  higher  test 
figure  since  it  would  not  have  been  advisable  to  do  so. 
The  patient  was  advised  to  use  60  grammes  of  starchy- 
food  daily  and  to  observe  two  days  a  week  when  no 
starch  was  taken. 

The  case  just  recorded  is  somewhat  out  of  the 
average  for  the  age  of  the  patient,  in  that  the  disease 
was  relatively  bland.  It  seems,  with  some  of  these 
cases  at  least,  as  though  their  freedom  from  symptoms 
depended  solely  upon  their  ability  and  fidelity  in  fol- 
lowing the  advice  given  them. 


194  DIABETES  MELLITUS 

The  following  patient  illustrates  in  the  history  of 
his  disease  the  transition  of  a  mild  into  a  severe  form 
of  diabetes. 

S.  G.  E.,  aged  fifty- four;  a  manufacturer,  came 
from  a  family  free  of  diabetic  taint.  There  had  been 
several  relatives  whose  lives  had  been  wrecked  because 
of  nervous  diseases. 

The  patient  first  noted  an  increase  in  urine  volume 
in  1910  and  because  of  this  he  consulted  his  physician. 
The  urine  then  contained  5  per  cent,  of  sugar.  A 
rest  was  advised  but  served  only  for  transient  benefit. 
Somewhat  later  there  was  considerable  annoyance 
from  cramps  in  the  legs  and  dyspnoea  on  exertion. 
The  appetite  was  good  but  easily  satisfied  and  thirst 
not  excessive.  Examination  revealed  no  fact  other 
than  that  the  patient  was  under  weight,  which  was 
normally  135  pounds;  but  at  the  beginning  of  the 
treatment  was  only  125  pounds.  The  urinary  analy- 
ses during  the  first  period  of  treatment  are  recorded 
in  the  following  table. 


Date. 
1911 
June 

Diet. 

Amount 

urine. 

c.c. 

Sugar. 
gm. 

Nitrogen. 
gm. 

Ketone, 
gm. 

19 

Liberal. 

2580 

80.5 

0 

21 

Test. . . 

2120 

36.2 

16.9 

0 

22 

C.  F... 

2070 

24.6 

0 

23 

C.  F... 

2620 

17.3 

0 

24 

Test. . . 

.       1850 

0 

0 

25 

C.  F... 

2050 

0 

0 

26 

C.  F... 

1640 

0 

NRVN  0.51 

0 

27 
28 

40  gm. 
C.  F... 

starch  (potato) . . . 

.      1460 

.       2880 

0 
0 

0 
0 

30 

100  gm 

.  bread 

2670 

0 

0 

TREATMENT  195 

Date.  Amount 

1911  urine.  Sugar.        Nitrogen.         Ketone. 

July  Diet.  c.c.  gm.  gm.  gm. 

1  C.  F 2060  0  0 

2  50  gm.  bread  and  100  of 

potato 2280  0  0 

3  C.  F 2670  0  13.7  0 

4  C.  F 2430  0  0 

5  150  gm.  bread 2610  0  0 

6  C.  F 2020  0  0 

7  100  gm.  bread  and  1  pt. 

champagne 3050  12.20  0 

8  C.  F 1680  0  0 

9  120    gm.    starch    (bread, 

peas,  potato) 2750  0  0 

10         120  gm.  starch 0  0 

This  record  shows  that  this  patient  utilized  some 
carbohydrate  at  the  beginning  of  this  treatment  and 
also  that  the  sugar  quickly  vanished  from  the  urine  on 
a  starch-free  diet.  An  increase  of  the  volume  above 
normal  even  after  the  glycosuria  had  ceased  was  due 
to  chronic  nephritis.  In  the  course  of  three  weeks  the 
ingest  of  starch  was  gradually  increased  up  to  120 
grammes  without  glycosuria.  He  was  directed  to  use 
the  equivalent  of  80  grammes  of  starch  daily  except- 
ing one  restricted  day  each  week  when  no  carbohy- 
drate was  to  be  taken.  The  urine  remained  free  of 
sugar  during  August  and  September  except  on  two 
occasions  when  traces  were  noted  (three  examinations 
weekly).  In  October  sugar  appeared  more  fre- 
quently, on  the  18th  amounting  to  44  grammes.  The 
diet  was  curtailed  but  there  was  glucose  excretion  even 
when  no  starch  was  ingested.  As  the  patient  ap- 
peared to  be  losing  ground  he  returned  for  a  second 


196  DIABETES  MELLITUS 

course  of  treatment  in  November.  The  result  of  this 
period  shows  the  transition  of  the  disease  to  a  severe 
type. 


Amount 

Datt 

urine. 

Sugar. 

Nitrogen. 

Ketone. 

November 

Diet. 

c.c. 

gm. 

gm. 

gm. 

24 

Test 

3400 

68.2 

14.6 

0 

25 

Test 

3320 

59.6 

15.4 

0 

26 

C.  F 

2780 

46.0 

15.2 

0 

27 

C.F 

. .  . . .      2890 

41.1 

NH3-N 

0.6     0 

28 

C.F 

3100 

36.0 

0 

29 

20  gm.  starch 

3240 

44.0 

0 

30 

C.F 

2630 

29 

0 

December 

1 

C.F 

2590 

19.0 

NH3-N 

0.81   0 

2 

C.F 

2640 

21.4 

0 

3 

2770 

31.2 

0 

4 

Vegetable  * 

2610 

10.6 

NH3-N 

0.78   0 

5 

C.  F 

2200 

0 

0 

6 

2490 

13.7 

0 

•  See  page  206. 

With  this  patient  the  urine  could  be  freed  of  sugar 
only  by  restricting  the  protein  food  as  well  as  the  car- 
bohydrate. During  several  months  of  treatment  it 
was  possible  to  bring  about  the  utilization  of  only  25 
grammes  of  ingested  starch  and  then  only  when  the 
starch  days  were  interpolated  in  a  manner  to  be  dis- 
cussed later.  The  encouraging  factor  in  cases  of  this 
sort  is  the  absence  of  acidosis  and  on  account  of  the 
perfect  metabolism  of  fats  this  food  may  be  given  in 
as  large  amounts  as  the  digestion  of  the  individual 
permits. 

The  failure  of  a  rigid  diet  to  effect  a  normal  urine 
within  a  few  days  is  commonly  accepted  as  evidence 


TREATMENT  197 

that  the  case  is  one  of  severe  diabetes  yet  this  is  by  no 
means  always  true.  Very  often  it  requires  some  time 
and  perseverance  to  attain  the  desired  result  in  pa- 
tients who  still  have  a  fair  tolerance.  The  glucose  ex- 
cretion with  these  cases  is  not  large,  10  to  15  grammes 
per  day  with  restricted  diets;  but  often  it  seems  al- 
most impossible  to  eliminate  this  small  amount.  The 
following  record  is  that  of  a  case  belonging  to  this 
category.  The  patient,  S.  R.,  was  a  banker  fifty- 
seven  years  of  age.  He  had  known  that  his  urine  con- 
tained sugar  for  about  four  years.  His  diet  during 
this  time  had  not  been  specially  restricted  although 
sweets  had  been  avoided.  The  urine  had  usually  con- 
tained about  2  per  cent,  of  sugar.  Several  months 
before  coming  to  me  he  had  a  bad  carbuncle.  This 
gave  him  much  annoyance  and  impaired  his  health, 
which  had  previously  been  excellent.  As  the  wound 
healed  very  slowly  his  physician  advised  him  to  take 
a  course  of  treatment  for  the  diabetes.  The  patient 
was  a  large  man  who  looked  angemic  and  pasty. 
Physical  examination  discovered  a  moderate  degree  of 
arteriosclerosis  in  his  radial  and  retinal  arteries,  but 
nothing  else  of  significance.  He  was  allowed  to  select 
his  own  food  during  the  first  two  days  in  the  hospital 
and  then  the  test  diet  was  ordered. 


198  DIABETES  MELLITUS 

Amount 


Date. 

urine. 

Sugar. 

Nitrogen 

Ketone, 

February 

Diet. 

c.c. 

gm. 

gm. 

gm. 

12 

1870 

66 

12 

....      1920 

72 

13 

Test 

....      1780 

58 

18.8 

0 

14 

....      1515 

45 

13.5 

0 

15 

....      1235 

19.8 

12.4 

0 

16 

....      1435 

8.6 

12.8 

0 

17 

....      1560 

4.7 

0 

18 

No  starch 

1610 

3.6 
4.9 

NH3-N  = 
12.1 

0.48  j  0 

19 

....      1435 

0 

20 

....      1375 

2.2 

0 

21 

....      1280 

0 

0 

22 

1600 

1.1 

0 

23 

1900 

0 

0 

24 

....      1640 

0 

0 

25 

No  starch 

1570 

0 
0 
0 

NH-N  = 

0.43    0 

26 

No  starch 

1880 

27 

1400 

28 

No  starch 

1930 

0 

March 

1 

....      1770 

0 

Increasing  amounts  of  starchy  foods  were  allowed 
every  other  day  until  70  grammes  were  being  used. 
No  sugar  was  found  during  the  period  of  observation, 
which  continued  till  March  18.  The  patient  gained 
eight  pounds  in  weight  during  the  last  two  weeks  of 
treatment.  He  was  instructed  to  observe  for  two 
months  longer  the  same  routine  employed  in  the  hos- 
pital and  was  allowed  to  return  home.  In  the  course 
of  the  following  ten  months  the  diet  was  further 
relaxed  so  that  the  patient  was  eating  daily  100 
grammes  of  carbohydrate,  as  bread  and  vegetables. 
Glycosuria  resulted  four  times  in  the  two  years  fol- 
lowing treatment,  and  he  was  well  at  last  report. 

One  asks  at  once  why  should  the  glycosuria  be  so 
intractable  in  a  case  which  proved  to  be  of  such  a  mild 


TREATMENT  199 

nature.  An  explanation  is  suggested  in  this  case  in 
the  results  of  the  analyses  of  blood  sugar.  On  Febru- 
ary 18  this  was  .13  gramme  per  cent,  and  on  the  24th 
it  had  fallen  to  0.09;  the  first  figure  scarcely  above 
normal  and  the  latter  below  the  summit  of  the  normal 
variation.  It  might  be  conjectured  that  here  we  have 
a  renal  element  in  the  picture;  at  least  there  was  no 
decreased  permeability  of  the  kidney  filter  such  as  is 
frequently  noticed  in  cases  of  this  type  resulting  in  a 
cessation  of  glycosuria  even  while  there  is  moderate 
hyperglycemia. 

During  the  course  of  rigid  treatment  such  as  that 
presented,  any  intelligent  patient  learns  a  good  deal 
with  regard  to  the  treatment  of  his  own  case.  It  is 
human  nature  that  when  the  methods  employed  meet 
with  success  the  patient  loses  respect  for  his  malady, 
arguing  that  what  has  been  done  once  he  can  do  again, 
and  the  consequence  often  is  that  after  he  has  gone 
from  under  the  scrutiny  of  his  adviser  he  gradually 
lapses  into  careless  habits  of  eating.  This  course  of 
events  is  inevitable  unless  the  directions  given  permit 
of  a  variety  in  diet  and  a  sense,  at  least,  of  freedom 
from  those  restraints  which  irk  us  all  at  times.  This 
is  the  reason  in  a  nutshell  why  the  effects  of  sanatorium 
treatment  and  "cures"  are  apt  to  be  of  brief  duration. 
The  treatment  ceases  when  the  patient  leaves  the  care 
of  the  physician  whose  advice  he  has  sought.     The 


200  DIABETES  MELLITUS 

brief  period  of  careful  observation  under  rigidly  con- 
trolled conditions  is  necessary  in  order  to  determine 
those  facts  on  which  future  treatment  depends.  This 
period  can  and  should  be  one  of  instruction  for  the 
patient  on  how  to  care  for  himself  so  that  afterwards 
he  can  cooperate  intelligently  with  his  medical  ad- 
viser. It  is  necessary  then  not  only  to  insist  upon  the 
patient's  help  but  also  allowing  for  human  weakness 
to  furnish  him  with  such  food  resources  that  he  will 
not  become  disgusted  and  fatigued  by  monotony.  The 
following  diet  scheme  I  have  employed  for  a  number 
of  years  with  cases  of  diabetes  where  the  tolerance 
was  not  so  restricted  as  to  make  it  impossible.  It  must 
be  stated  emphatically  that  this  method  cannot  be  used 
with  severe  cases. 

As  the  word  "unit"  conveys  a  more  definite  mean- 
ing to  a  patient  than  "ten  grammes"  a  table  was  con- 
structed on  a  unit  basis ;  ten  grammes  of  carbohydrate 
is  here  expressed  as  one  unit;  twenty  grammes,  two 
units,  etc.  In  constructing  this  table  approximations 
only  are  considered;  if  a  tablespoonful  of  a  cooked 
food  contains  on  analysis  12.5  grammes  of  starch  it  is 
recorded  as  one  unit,  likewise  another  food  may  actu- 
ally contain  but  8  grammes  of  starch;  it  is  also  re- 
corded as  one  unit  (10  grammes).  An  average  is 
struck  in  the  errors.  As  a  matter  of  fact  these  ap- 
proximations work  out  very  close  to  actual  weight  as 


TREATMENT  201 

I  have  found  by  allowing  patients,  whose  tolerance  had 
been  tested  repeatedly  and  found  constant,  to  use  a 
given  number  of  units  from  the  table.  One  patient 
whose  tolerance  was  found  constantly  to  be  80 
grammes  of  carbohydrate  was  given  nine  units  on 
three  different  occasions  and  there  was  recovered  from 
the  urine  8.7,  10.4,  7.9  grammes  of  sugar  respectively 
for  these  three  days;  that  is,  the  diet  was  approxi- 
mately ten  grammes  in  excess  of  the  amount  utilized 
and  the  urinary  sugar  disclosed  the  degree  of  approxi- 
mation. 

Soups. 

Bean average  portion equals  1  unit. 

Clam  chowder average  portion equals  1  unit. 

Cream  of  corn average  portion equals  1  unit. 

Pea  puree average  portion equals  1  unit. 

Potato average  portion equals  1  unit. 

Vegetables. 

Beans,  baked 2  tablespoonfuls equal   2  units. 

Beans,  butter 2  tablespoonfuls equal    1  unit. 

Beans,  lima 2  tablespoonfuls equal    2  units. 

Beans,  kidney 2  tablespoonfuls equal    2  units. 

Beets 2  tablespoonfuls equal    1  unit. 

Corn,  canned 2  tablespoonfuls equal   2  units. 

Corn,  green 1  ear equals  2  units. 

Onions 2  onions equal    1  unit. 

Green  peas 2  tablespoonfuls equal    1  unit. 

Potato,  baked 1  medium  sized equals  3  units. 

Potato,  boiled 1  medium  sized equals  3  units. 

Potato,  mashed 2  tablespoonfuls equal   2  units. 

Fruit. 

Apple 1  medium  sized equals  2  units. 

Blackberries 2  tablespoonfuls equal    1  unit. 

Cantaloupe one-half equals  2  units. 

Currants 3  tablespoonfuls equal   1  unit. 

Huckleberries 2  tablespoonfuls equal    1  unit. 

Orange 1  medium  sized equals  2  units. 

Peach 1  medium  sized equals  1  unit. 

Pear 1  medium  sized equals  2  units. 

Plum 2  medium  sized equal    1  unit. 

Raspberries 3  tablespoonfuls equal    1  unit. 

Strawberries 4  tablespoonfuls equal    1  unit. 

14 


202  DIABETES  MELLITUS 

Cereals. 

Bread slice  3X4X  V2  inches. . equals  2  units. 

Hominy,  boiled 1  tablespoonful equals  1  unit. 

H— O,  boiled 2  tablespoonfuls equal    1  unit. 

Macaroni,  boiled 2  tablespoonfuls equal   2  units. 

Macaroni,  baked  with  cheese 2  tablespoonfuls equal   2  units. 

Oatmeal,  boiled 2  tablespoonfuls equal    1  unit. 

Rice,  boiled 1  tablespoonful equals  2  units. 

Shredded  wheat  biscuit 1  biscuit equals  2  units. 

Spaghetti,  baked  with  tomato 2  tablespoonfuls equal   2  units. 

Sample  Day  (6  units  allowed,  i.e.,  60  grammes  starch). 

Breakfast: 

Ham,  eggs. 

Cereal  (equal  to  1  unit)  with  tablespoonful  cream. 
Lunch: 

Clear  broth. 

Meat,  green  vegetable. 

Baked  potato  (equal  to  3  units). 

Dinner: 
Soup. 

Meat,  green  vegetable. 

Boiled  rice  (1  tablespoonful  equal  to  2  units). 
Salad  and  cheese. 

Foods  on  the  list  that  are  not  suited  to  an  in- 
dividual case  are  of  course  crossed  off. 

The  advantage  of  a  scheme  of  this  character  to  the 
patient  is  that  he  is  enabled  to  select  for  himself  what 
he  will  eat.  He  is  restricted  only  in  quantity.  In  a 
surprisingly  short  time  patients  memorize  the  equiva- 
lents without  special  effort.  For  those  cases  where 
the  tolerance  is  above  fifty  grammes  the  plan  works 
well  in  practice.  With  more  severe  types  the  toler- 
ance is  apt  to  be  too  fluctuating  a  factor  to  permit 
of  this  procedure. 

Finally  these  individuals  must  observe  at  definite 
intervals  strict,  carbohydrate-free  days  of  diet.  The 
object  of  this  is  not  to  strain,  so  to  speak,  the  degree 
of  tolerance  previously  established.     It  is  to  be  re- 


TREATMENT  203 

garded  as  a  rest  day  for  a  function.  In  the  beginning 
these  days  may  be  required  frequently,  two  a  week; 
later  if  all  goes  well,  less  frequently.  As  a  rule  I  ad- 
vise every  tenth  day,  at  least,  with  even  the  mildest 
cases  as  a  carbohydrate-free  day. 

The  second  and  third  division  of  cases  as  deter- 
mined by  the  urine  analyses  (sugar  more  than  50 
grammes ) ,  incorporates  those  where  there  is  a  failure 
to  utilize  ingested  carbohydrate.  This  failure  of  func- 
tion may  or  may  not  be  accompanied  by  defective  fat 
metabolism  manifested  as  ketonuria.  Even  when 
there  is  no  ketonuria  one  must  constantly  bear  in  mind 
with  these  cases  that  there  is  this  tendency  and  that 
it  is  much  easier  to  prevent  acidosis  than  it  is  to 
overcome  it. 

The  following  case,  a  man  of  thirty-six  years  of 
age,  is  one  that  appeared  to  be  very  severe  but  has  by 
careful  adherence  to  diet  kept  in  health  for  four  years. 
The  patient  first  noted  increased  urination  at  night  in 
1909.  At  this  time  he  was  working  very  hard  in  the 
capacity  of  electrical  engineer  in  a  large  manufactory. 
His  physician  told  him  that  he  had  diabetes  and  ad- 
vised that  he  abstain  from  sugar  and  use  gluten  bread. 
He  did  this  and  sent  his  urine  frequently  to  a  chemist 
for  analysis.  During  1909  the  urine  volume  seldom 
exceeded  two  litres  with  an  average  of  about  60 
grammes  of  sugar.  In  1910  he  lost  some  weight  and 
contracted  "grip,"  which  left  him  very  weak.     He 


204 


DIABETES  MELLITUS 


made  a  very  slow  convalescence  and  noted  that  he  was 
passing  more  urine  than  previously.  His  physician 
became  alarmed  about  him  and  advised  him  to  take 
a  course  of  treatment.  The  following  table  is  ab- 
stracted from  his  record  which  covers  nine  weeks. 

The  result  of  the  test  diet  indicates  that  the  pa- 
tient was  utilizing  no  starch  and  not  all  the  sugar 
derived  from  the  protein  food.  The  sole  hopeful  ele- 
ment in  the  case  in  the  beginning  was  the  absence  of 
any  signs  of  acidosis.  There  is  not  the  response  to 
restricted  diet  noted  in  the  milder  cases ;  the  urine  can 
be  made  free  of  glucose  but  only  by  restricting  the 
protein  ingest  as  well  as  excluding  starch.  At  first 
this  measure  appeared  to  effect  no  lasting  benefit 
since  there  was  at  once  a  return  of  the  glycosuria. 


Amount 

Date. 

urine. 

Sugar. 

Nitrogen. 

NH 

Ketone. 

Weight 

Octobei 

Diet. 

C.C. 

gm. 

gm. 

gm. 

gm. 

lb. 

19 

Test  3d  day 

3300 

79 

23.2 

.46 

0 

158 

20 

C.  F.. 

2780 

61 

19.6 

0 

158 

21 

C.  F.. 

2400 

28 

18.4 

!57 

0 

157 

22 

Test.. 

3100 

68 

17.5 

0 

23 

C.  F.. 

2580 

41 

18.1 

!58 

0 

24 

C.  F.. 

2200 

19 

16.6 

0 

156 

November 

6 

Vegetable 

1920 

14 

12.5 

.68 

+ 

7 

C.  F.. 

1710 

0 

17.2 

+ 

8 

C.  F.. 

1820 

11 

17.8 

.11 

+ 

154 

9 

Vegetable 

1240 

0 

13.1 

.68 

+ 

20 

Vegetable 

1310 

0 

12.8 

.57 

+ 

154 

21 

C.  F.. 

1280 

0 

15.6 

... 

0 

22 

C.  F.. 

1380 

0 

14.9 

. . . 

0 

23 

Test.. 

1410 

31 

15.7 

. . . 

0 

154 

December 

17 

C.  F 

1370 

0 

14.9 

.  * . 

0 

18 

20  gm. 

1500 

trace 

16.3 

. . . 

0 

155 

19 

C.  F 

1490 

0 

16.8 

... 

0 

20 

30  gm. 

bread. , . 

1370 

0 

14.2 

... 

0 

155 

27 

Test 

1510 

14 

14.9 

. . . 

0 

155.5 

TREATMENT  205 

It  is  evident  from  the  latter  part  of  the  record 
that  more  starch  was  then  being  consumed  by  the 
tissues  than  in  the  beginning;  in  fact  about  30 
grammes.  The  patient  was  directed  to  use  this  rou- 
tine: one  day  30  grammes  of  bread,  then  a  vegetable 
day  and  on  the  third  day  no  starch.  He  was  intelli- 
gent, appreciated  the  gravity  of  his  condition  and 
obeyed  instructions.  In  the  course  of  the  next  six 
months  his  condition  improved  so  much  that  he  re- 
sumed his  work.  His  tolerance  has  never  been  better 
than  about  50  grammes  of  carbohydrate,  but  with 
care  he  has  preserved  this  and  has  been  able  to  main- 
tain fair  health  and  freedom  from  disturbing  symp- 
toms. 

With  cases  of  the  severer  types,  eliminating  the 
carbohydrate  from  the  diet  is  not  sufficient  to  control 
the  glycosuria.  It  is  necessary  to  reduce  also  the  pro- 
tein ingested.  The  meaning  of  this  is  that  the  body  is 
not  able  to  utilize  all  the  sugar  derived  from  protein. 
When  the  carbohydrates  are  excluded  from  the  diet 
and  the  protein  much  reduced  there  is,  of  course,  an 
increase  of  fat  metabolism  to  furnish  the  necessary 
energy  for  body-heat  maintenance.  In  other  words, 
the  conditions  of  diet  are  those  which  induce  ketonuria 
and  since  with  the  severe  types  of  diabetes  there  is 
usually  found  some  diacetic  acid  in  the  urine  before 
the  diet  is  curtailed  it  is  evident  that  these  restrictions 


206  DIABETES  MELLITUS 

must  be  conducted  with  considerable  care  in  order  to 
avoid  alarming  symptoms.  The  following  diet  is  one 
I  commonly  employ  when  protein  is  to  be  restricted : 

Breakfast: 

Spanish  omelette  of  yolks  of  3  eggs  with  tomatoes,  parsley,  and 
mushrooms. 

One  large  cup  of  coffee  with  a  tablespoonful  of  cream. 
Luncheon : 

A  cup  of  bouillon,  a  large  plate  of  asparagus  with  egg  sauce. 
4  p.m.  : 

A  cup  of  coffee  or  a  glass  of  wine  with  one  casoid  biscuit. 
Dinner: 

A  cup   of  bouillon,  1  box  of  Norwegian  sardines,  a  large  portion 
of  boiled  spinach  with  oil  or  butter. 

A  glass  of  wine  or  whiskey  and  water.5 

When  this  "vegetable  day"  is  employed  it  is  ad- 
visable to  give  alkalies;  twenty  grammes  of  soda  bi- 
carbonate may  be  given  during  the  day  with  lemon 
juice  as  a  palatable  beverage.  The  object  of  this  diet 
is  to  reduce  the  glycosuria  by  restricting  the  protein 
ingested.  Its  use  is  indicated  when  the  glucose  ex- 
cretion persists  in  spite  of  a  carbohydrate-free  diet. 
There  are  also  some  cases,  as  has  been  already  men- 
tioned, where  a  trifling  glucose  excretion  (5  to  10 
grammes)  persists,  notwithstanding  a  restricted  diet; 
and  with  these  cases  a  vegetable  day  is  a  convenient 
way  of  hastening  the  desired  end.  It  not  infrequently 
happens  that  a  slight  degree  of  ketonuria  first  appears 
on  vegetable  days  and  vanishes  promptly  as  the  diet 

5  With  much  restricted  diets  it  is  impossible  to  supply  an  adequate 
caloric  value.     Loss  in  weight  is  for  a  time  inevitable. 


TREATMENT  207 

is  changed.  Occasionally,  on  the  other  hand,  a  keto- 
nuria  of  decided  degree  drops  quite  suddenly  follow- 
ing a  vegetable  day.  With  the  latter  cases  there  is 
always  a  coincident  diminution  in  the  amount  of  glu- 
cose excreted.  The  following  record  illustrates  this 
fact.  The  patient  was  a  young  man  who  had  been 
under  treatment  for  some  time  before  he  was  admitted 
to  the  hospital.  The  urine  had,  at  times,  contained 
over  100  grammes  of  sugar  on  a  restricted  diet.  The 
family  physician  reported  that  there  had  been  a 
positive  ferric  reaction  for  over  a  month. 

Total 
Date.  Sugar.         Nitrogen.      Ammonia.       ketones. 

January  Diet.  gm.  gm.  gm.  gm. 

14  C.  F 68  16.4  2.7  6.4 

24  Vegetable 11  11.4  2.9  7.1 

26  C.  F 3  15.8  1.3  4.6 

30  C.  F 5  16.1  0.8  .7 

The  vegetable  diet  in  this  case  did  not  free  the 
urine  of  glucose  but  the  amounts  of  sugar  excreted 
in  the  following  days  indicated  that  more  was  being 
consumed  in  the  tissues  and  a  fall  in  the  ketone  elimi- 
nation is  the  expression  of  this  improved  metabolism. 

Since  with  severe  diabetes  the  acidosis  demands 
as  much  or  more  consideration  than  the  glucose  ex- 
cretion the  diet  has  also  to  be  arranged  to  meet  this 
indication.  All  endeavors  to  combat  acidosis  are, 
fundamentally,  efforts  to  increase  the  amount  of  car- 
bohydrate burned  in  the  tissues.  Fats  are  burned  in 
the  fire  of  carbohydrate  and  our  efforts  are  directed 
toward  facilitating  this  combustion.     There  are  two 


208  DIABETES  MELLITUS 

principles  involved  as  a  result  of  observation:  first, 
some  starches  are  better  utilized  than  others  and  this  is 
true  even  though  we  cannot  differentiate  chemically 
between  these  starches ;  second,  a  given  starch  is  better 
cared  for  when  it  is  given  to  the  body  with  a  minimum 
of  other  food  substance.  The  reasons  for  these  facts 
are  not  apparent  in  the  light  of  our  present  knowledge 
yet  there  seems  no  question  of  the  validity  of  the  facts. 
The  application  of  these  principles  finds  its  expression 
in  the  rice,  potato,  and  oatmeal  "cures."  With  all 
alike,  to  produce  the  desired  result  it  is  necessary  to 
confine  the  diet  for  a  period  to  one  of  these  foods. 
Oatmeal  alone  is  a  valuable  food  for  decreasing  ketone 
formation  but  when  used  with  meats  and  vegetables 
its  effect  is  much  impaired.  At  best  it  is  combined 
only  with  some  butter  fat  to  increase  the  caloric  value. 
That  oatmeal  diminishes  acidosis  by  reason  of  increas- 
ing the  amount  of  carbohydrate  utilized  in  the  body 
is  conjectured  but  is  not  adequately  attested  by  the 
respiratory  quotient  observed  after  oatmeal  diets 
when  there  is  no  decrease  in  the  glycosuria.  With 
some  cases  other  forms  of  starch  than  oatmeal  can  be 
employed  provided  they  are  given  in  the  same  way, 
that  is,  in  combination  with  a  minimum  of  protein 
food.  Wheat  flour,  for  example,  I  have  used  as  a 
porridge  and  as  bread  (bread  and  butter  days).  Be- 
fore illustrating  the  use  of  these  diets  with  specific 
cases  attention  should  be  directed  to  their  limitations. 


TREATMENT  209 

In  the  first  place  it  is  usually  not  possible  to  employ 
these  carbohydrate  diets  for  more  than  a  few  days 
no  matter  how  urgent  the  need  since  patients  so 
quickly  tire  of  them.  Then,  too,  the  desired  result 
does  not  invariably  follow.  Oatmeal  is  more  apt  to 
work  well  than  other  forms  of  starch  but  with  some 
cases  there  is  no  resulting  fall  in  the  ketonuria  with 
this  diet  and  in  this  event  other  forms  of  starch  should 
be  tried.  Occasionally  starch  diets  induce  tympanites 
so  severe  that  the  patient  cannot  endure  the  discom- 
fort. 

These  starch  diets  as  I  have  employed  them  are  as 
follows : 

Oatmeal  Diet. 

Cook  in   a   double  boiler   for   at  least   six   hours   ten  ounces   of 
oatmeal  in  two  quarts  of  water,  slightly  salted.    While  still  hot 
strain  through  a  sieve  and  add  three  ounces  of  butter,  stirring 
well. 
This  is  the   food  allowance   for  one  day.     A  cupful   every  two 
hours. 
Potato  Diet. 
Breakfast: 

One  baked  potato  with  butter. 
One  cup  of  coffee  with  25  c.c.  cream. 
Lunch  and  dinner: 

Potato,  boiled  with  skin,  butter. 
Green  vegetable,  wine  or  whiskey. 
Bread  and  Butter  Day. 
Breakfast: 

Two  pieces  of  bread  or  toast,  buttered. 
Two  egg  yolks  cooked  any  style. 
Lunch  and  dinner: 

Two  pieces  of  bread  and  butter. 
Green  vegetable  with  egg  sauce  or  oil. 
A  rasher  of  bacon. 
Coffee,  wine,  whiskey. 


210  DIABETES  MELLITUS 

These  diets  find  their  chief  usefulness  in  reduc- 
ing dangerous  degrees  of  acidosis,  and  since  alcohol 
is  very  often  an  important  aid  to  that  end  I  commonly 
advise  a  dry  wine  or  whiskey  with  soda. 

In  some  cases  (and  I  have  observed  this  most  fre- 
quently with  children)  the  oatmeal  diet  serves  not 
only  to  reduce  ketonuria  in  a  remarkable  way  but  the 
glycosuria  diminishes  also.  Several  times  I  have  seen 
children,  with  whom  the  sugar  and  ketone  excretion 
portended  a  rapid,  fatal  issue  of  the  disease,  respond 
to  two  days  of  oatmeal  diet  by  complete  disappearance 
of  the  sugar  from  the  urine.  Although  this  result 
with  the  majority  means  only  a  postponement  of  the 
inevitable,  even  then  it  is  worth  while. 

The  application  of  the  principles  concerned  with 
the  use  of  these  special  diets  is  best  illustrated  by  ab- 
stracts from  the  records  of  cases  of  severe  diabetes. 
And  in  the  selection  of  cases  I  have  used  only  those 
where  there  was  not  only  an  obstinate  glycosuria  but 
also  a  more  or  less  dangerous  degree  of  acidosis. 

The  first  case  is  that  of  a  man  thirty-three  years  of 
age,  who  entered  the  hospital  in  a  weak  and  emaciated 
condition  with  the  usual  symptoms  of  severe  diabetes. 
There  was  a  pronounced  ketonuria,  which  was  the  chief 
factor  considered  in  the  early  part  of  his  treatment. 
While  the  sugar  output  was  influenced  to  a  consider- 
able extent  the  urine  never  became  free  of  glucose. 
The  degree  of  success  with  cases  of  this  sort  is  meas- 


TREATMENT  211 

ured  by  the  fall  in  the  ketonuria  (and  ammonia)  and 
the  increase  in  the  patient's  weight  and  sense  of  well 
being.  The  influence  of  the  various  forms  of  diet  is 
notable.  Oatmeal  did  not  apparently  diminish  glu- 
cose excretion  but  there  was  a  decline  in  the  amounts  of 
the  ammonia  and  ketone  bodies.  In  December  a  rou- 
tine was  advised  as  follows :  an  oatmeal  day,  to  be  fol- 
lowed by  one  when  no  starch  was  taken ;  then  a  vege- 
table day  followed  again  by  a  carbohydrate-free  day. 
The  chart  is  abstracted  from  the  record. 

Date.  Amount 

urine.     Sugar.  Nitrogen.  Ammonia.  Diacetic.  /3-oxy.      Weight. 

September  Diet.  c.c.  gm.  gm.  gm.  gm.  gm.  lb. 

14     Unrestricted 9050  572  28.  2.14  +  +  124 

17  Test 4400  220*      18.  2.00  +  + 

18  50  gm.  bread. . . .  5600  308  +     + 

19  50  gm.  bread..  ..  5300  302  ...    2.22  7.68  4.87 

20  50  gm.  bread. . . .  1950  121 

21  50  gm.  bread. . . .  3100  155 

22  Oatmeal 3200  173  12.4    1.23  +     + 

23  Oatmeal 3000  162 

24  C.  F 3700  178  +     + 

25  C.  F 1700   75 

26  50  gm.  bread. . . .  4500  201  16.4     .87  +     +    123 

27  Vegetable 2400   72  14.2    1.82  4.03  2.17 

28  C.  F 3200   80  +     +    124 

October 

14  Oatmeal 2300  82  +  + 

15  Oatmeal 2600  91  13.2    .82  +  +    126 

16  Vegetable 2400  77  14.8    1.23  -f  + 

17  C.  F 2700  96  ...    1.14  +  +    129 

November 

26  Oatmeal 2400  88  .77    +     + 

28  C.  F 2050  59 

30  C.  F 2140  94    ...     .69    +     +    133 

December 

4  C.  F 2500  101    +  + 

6  C.  F 3000  84    1.34  .72 

8  C.  F 1650  52  15.7    .68    +  +    135 

*  When  the  sugar  excretion  is  so  large  one  suspects  that  food  was  taken  that  was  not  re- 
po  ted.    Many  severe  cases  are  no  more  trustworthy  than  morphine  habitues. 


212  DIABETES  MELLITUS 

This  patient  remained  fairly  well  during  the  winter 
and  pursued  his  work.  In  May  he  contracted  pneu- 
monia and  after  defervescence  diabetic  coma  super- 
vened, from  which  he  died. 

Whether  this  patient's  resistance  to  infection 
would  have  been  appreciably  increased  by  permitting 
us  to  carrv  out  a  course  of  treatment  that  would  free 
the  urine  of  sugar  we  may  only  conjecture.  These 
cases — and  they  are  numerous — represent  what  the 
patient  will  do  for  himself,  not  what  it  is  possible  to 
accomplish  with  severe  diabetes.  The  following  two 
cases  adhered  rigidly  to  the  dietetic  restrictions  im- 
posed upon  them,  with  the  result  that  the  sugar  dis- 
appeared from  the  urine  and  an  acidosis  of  menacing 
severity  subsided. 

The  first  case  is  that  of  a  man  twenty-six  years  of 
age,  with  a  history  of  diabetes  in  his  family.  His  dia- 
betes had  been  of  excessive  severity  with  rapid  loss  in 
weight  and  the  early  symptoms  of  acidosis.  At  the 
commencement  of  his  treatment  he  was  very  drowsy 
and  retained  but  little  taken  into  the  stomach.  For 
thirty-six  hours  treatment  consisted  exclusively  in  ad- 
ministering alkalies  (intravenously  and  by  rectum) 
and  whiskey  (by  mouth) .  The  patient  was  then  given 
small  amounts  of  oatmeal  gruel  for  two  days,  followed 
by  two  strict  vegetable  days  (the  vegetable  diet  of 
p.  206,  excluding  eggs  and  fish).  On  the  fifth  day, 
April  4,  the  diet  was  carbohydrate-free. 


TREATMENT  213 

Amount 
Date.  urine.         Sugar.       Nitrogen.  NHa— N  Weight. 

April  Diet.  c.c.  gm.  gm.  gm.  lbs. 

4  C.F 2600  44.4  18.1  3.4  137 

10  C.F 2540  18.0  8.4  1.8  135 

13  Vegetable 2300  0  9.1  1.4  135 

16  C.F 2225  9.1  ...  0.8 

18  Vegetable 2025  8.3 

21  C.F 2300  4.6  29.2  0.6  136 

29  Vegetable 2010  0  137 

May 

4  20  gms.  starch 1700  0             31.3         0.6         139 

15  30  gms.  starch 2225  trace 

21  30  gms.  starch 1875  0  141 

June 

1   40  gms.  starch 1780    0      143 

26   60  gms.  starch 1500    0      147 

September 

29      60  gms.  starch 1870  0  152 

Two  strict  vegetable  days  were  followed  by  days 
of  carbohydrate-free  diet  in  rotation  until  April  18, 
after  which  but  two  vegetable  days  were  given  each 
week.  After  May  4  the  vegetable  days  were  discon- 
tinued, but  starchy  food  was  used  only  on  alternate 
days,  and  on  one  day  each  week  protein  food  was  con- 
fined to  eggs  and  fish.  This  patient  gave  complete 
and  intelligent  cooperation.  He  is  apparently  in  per- 
fect health  at  present,  although  confined  strictly  to 
his  diet. 

The  second  example  is  that  of  a  man  twenty-three 
years  of  age,  who  appeared  to  me  to  be  beyond  help 
when  I  first  saw  him.  The  patient  had  been  confined 
to  bed  for  three  days  because  of  weakness  and  drowsi- 
ness. He  could  be  roused  to  answer  questions  but 
dozed  off  while  attempting  to  converse.     The  urine 


214  DIABETES  MELLITUS 

analysis  showed  4.13  grammes  of  ammonia  nitrogen 
and  219  grammes  of  sugar.  The  prognosis  seemed 
almost  hopeless. 

Infusions  of  alkalies  were  given  and  wine  as  a 
beverage.  No  food  was  offered  the  patient  for  the 
first  thirty-six  hours,  then  he  was  given  oatmeal  gruel. 
The  chart  shows  the  details  of  the  treatment. 

Amount 
Date.  urine.        Sugar.       NHa— N      Diacetic. 

October  Diet.  c.c.  gm.  gm.  gm. 

13  Oatmeal 1260  56.7  2.43  -4~f-  + 

15  Oatmeal 640  16.6  1.85  ++  + 

16  Vegetable,  strict 910  11.8  . . .  ++  + 

17  Vegetable,  strict 890  7.6  0.95  +++ 

19  Oatmeal 860  1.2  ...  -f 

21  Vegetable,  strict 780  0  ...  -f 

22  20  gms.  starch 560  0  ...  + 

23  20  gms.  starch 1380  0  0.55  trace 

26  Vegetable 1580  0 

November 

12  60  gms.  starch 1460  5.8 

13  C.F 1280  0 

15       20  gms.  starch 1320  0 

In  attempting  these  very  rigid  courses  of  treat- 
ment there  are  certain  indispensable  conditions:  the 
patient  must  be  either  in  a  hospital  or  under  the  abso- 
lute control  of  a  nurse  who  understands  diabetic  diets. 
The  cooperation  of  the  family  can  be  expected  in  sym- 
pathy but  not  to  the  extent  of  denying  the  patient 
food.  After  the  critical  period  is  passed  the  immediate 
cooperation  of  the  patient  is  absolutely  necessary.  It 
requires  no  little  fortitude  in  a  patient  to  submit  to 
this  routine.  The  substitution  of  some  bulky  food  for 
the  fast  days  advocated  by  Naunyn  does  not  very 


TREATMENT  215 

materially  assuage  the  pangs  of  hunger.  The  mode 
of  operation  of  this  regimen  is  not  very  clear  except 
that  there  is  given  an  opportunity  for  a  fall  in  blood 
sugar.  Naunyn  advocated  fast  days  to  meet  this  end 
and  used  several  in  succession  with  severe  cases.6  The 
ration  of  green  vegetables  is  a  somewhat  less  heroic 
measure  to  this  same  end.  Alcohol  is  a  most  valuable 
therapeutic  agent  in  acidosis,  as  Neubauer  demon- 
strated, and  should  be  used  liberally. 

In  the  treatment  of  these  severe  cases  of  diabetes 
where  acidosis  is  the  chief  consideration  it  is  not  suffi- 
cient to  advise  a  suitable  diet.  The  patients  react 
to  the  slightest  fatigue  by  an  increase  in  the  ketonuria, 
hence,  it  becomes  necessary  to  insist  on  absolute  rest 
in  bed.  The  amounts  of  alkalies  given  depend  on 
the  ability  of  the  patient  to  take  them.  Twenty-five 
grammes  of  bicarbonate  of  soda  a  day  is  easily  given, 
with  more  than  this  it  facilitates  administration  with 
some  cases  to  prescribe  the  soda  in  enteric  capsules. 

By  the  enforcement  of  rest  in  bed  and  a  stringent 
diet  the  urine  can  be  freed  of  sugar  in  the  vast  ma- 
jority of  cases.  With  early  cases  the  result  is  often 
effected  within  a  few  days;  when  the  disease  is  ad- 

6  In  an  endeavor  to  test  the  Lusk  ratio  with  severe  cases  of  diabetes 
several  years  ago,  I  observed  a  fall  in  ketone  excretion  after  the  use  of 
very  meagre,  rigid  diets,  even  when  alkalies  were  given  liberally.  This 
appeared  as  a  basis  for  therapeutic  restrictions  and  has  since  been  em- 
ployed, although  it  is  against  ideas  commonly  taught.  I  believe  there  is 
no  danger,  especially  when  alcohol  is  used  as  a  safeguard. 


216  DIABETES  MELLITUS 

vanced  and  there  is  a  complicating  severe  acidosis 
months  may  be  necessary — and  for  the  treatment  of 
these  most  severe  types  of  the  disease  no  method  is  of 
more  benefit  than  the  employment  of  vegetable  days 
and  fast  days  as  advocated  by  Naunyn.  These  are  the 
most  discouraging  cases,  as  they  never  approach  a 
semblance  of  health.  While  it  is  possible  to  free  the 
urine  of  sugar  and  to  build  up  some  tolerance  so  long 
as  the  patient  is  in  bed  and  in  hospital,  at  once  on  be- 
ing released  from  incessant  control  there  is  an  inevita- 
ble transgression  beyond  the  path  of  safety  in  diet  and 
exercise.  Life  under  the  necessary  conditions  is  not 
worth  living  for  all  but  the  very  few. 

With  severe  cases  of  diabetes  coma  develops  finally 
in  spite  of  the  best  endeavors.  The  only  means  we 
have  at  present  for  treating  this  condition  is  with 
alkalies.  Large  amounts  of  sodium  bicarbonate  or 
carbonate  must  be  introduced  into  the  body  in  order 
to  produce  any  effect.  Where  coma  is  already  de- 
veloped an  infusion  into  a  vein  is  necessary  and  this 
may  be  supplemented  by  enemata.  For  intravenous 
infusions  one  uses  sodium  carbonate  in  four  per  cent, 
solution.  The  sodium  salt  is  added  to  sterile  water,  as 
boiling  changes  the  carbonate  into  the  bicarbonate. 
Of  this  solution  250  c.c.  may  be  given  every  four  hours. 
The  technic  of  administration  is  simple  and  essentially 
the  same  as  that  employed  in  giving  salvarsan,  the 
only  apparatus  necessary  being  a  needle  of  about  20 


TREATMENT  217 

gauge.  In  stress  of  circumstance  a  douche  bag  may 
be  used  as  the  reservoir.  The  solution  should  be  given 
slowly  with  not  more  than  three  feet  of  elevation  of 
the  reservoir.  When  coma  is  not  pronounced  this 
measure  is  occasionally  successful.  The  best  way  of 
giving  enemata  is  by  the  Murphy  drip  with  which 
four  per  cent,  bicarbonate  of  soda  in  physiological  salt 
solution  can  be  given  continuously.  This  procedure 
has  the  added  advantage  of  introducing  considerable 
fluid  into  the  body. 

Luthje  believes  that  sugar  isf  better  utilized  by 
diabetics  when  given  by  rectum  and  advises  the  em- 
ployment of  enemata  of  glucose  solutions  in  severe 
acid  intoxication. 

SURGICAL    COMPLICATIONS 

The  complications  of  diabetes  which  require  sur- 
gical treatment  can  best  be  considered  under  two  divi- 
sions :  first,  those  disorders  where  the  primary  disease 
is  an  impeding  factor  to  the  healing  process;  and 
under  this  head  the  infections  take  first  rank :  second, 
those  disorders  wherewith  any  surgical  operation  be- 
comes hazardous  on  account  of  the  danger  of  coma 
diabeticum. 

Every  diabetic  is  prone  to  infections  such  as  boils, 
carbuncles,  and  various  phlegmons ;  and  with  the  older 
patients  perforating  ulcers.  The  so-called  diabetic 
gangrene  and  osteomyelitis  are  very  common.    All  of 

15 


218  DIABETES  MELLITUS 

these  conditions  often  require  some  surgical  treatment 
in  the  beginning;  pus  collections  must  be  opened  and 
drained.  After  this  initial  measure  it  is  a  matter  of 
common  observation  that  healing  of  the  wound  is  ex- 
cessively sluggish  at  best  and  often  the  area  involved 
extends.  This  state  of  affairs  is  best  exemplified  with 
boils  and  carbuncles  which  in  diabetes  may  assume 
menacing  severity.  One  bad  boil  after  another  ap- 
pears and  is  opened,  the  patient  between  physical 
discomfort  and  the  infection  loses  weight  and  strength, 
becoming  constantly  less  able  to  withstand  new  in- 
vasions. Death  may  occur  from  septicaemia.  The 
failure  of  these  wounds  to  heal  is  due  fundamentally 
to  the  fact  that  the  blood  and  tissue  juices  contain  an 
abnormally  large  amount  of  glucose.  This  glucose 
not  only  hampers  the  ordinary  reparative  reactions 
in  the  tissues  but  it  also  furnishes  a  better  culture 
medium  for  infecting  organisms  than  normal.  The 
proof  of  this  contention  is  found  in  the  rapid,  and  at 
times,  astonishing  improvement  that  follows  the  suc- 
cessful dietetic  treatment  of  the  diabetes.  The  cases 
that  are  most  apt  to  present  these  surgical  complica- 
tions are  adults  over  forty  years  of  age  where  the  dia- 
betes is  of  a  relatively  mild  type  which  responds  to 
appropriate  treatment.  Acidosis  is  but  seldom  a 
menacing  factor.  The  following  case  is  an  example. 
The  patient  was  a  man  fifty-two  years  of  age  who  had 


TREATMENT  219 

had  diabetes  some  six  years.  He  had  been  advised  to 
abstain  from  sweets  and  to  use  gluten  bread.  For  the 
last  year  he  had  had  considerable  inconvenience  from 
boils  on  various  parts  of  the  body.  For  about  two 
months  he  had  a  large  carbuncle  on  the  back  which 
was  opened  and  still  drained  freely;  shortly  after  this 
operation  a  painful  swelling  appeared  in  the  left  side 
of  the  abdomen  and  was  incised;  since  this  last  opera- 
tion there  have  been  some  half  dozen  boils  on  the  arms 
and  shoulders.  The  patient  had  lost  about  thirty 
pounds  in  weight  during  six  months.  There  was  a 
wound  with  sluggish  granulations  and  much  discharge 
in  the  left  infraspinatus  region  and  in  the  left  rectus 
muscle  just  above  the  umbilicus  an  ulcer  two  by  three 
inches,  surrounded  by  a  wide  area  of  induration.  The 
ulcer  surface  was  dark  in  color  and  discharging  freely ; 
granulations  were  almost  absent.  The  urine  contained 
48  grammes  of  sugar.  It  required  six  days  to  free  the 
urine  of  glucose  and  on  the  tenth  day  the  surgeon  re- 
ported that  the  ulcers  were  clean  and  granulation 
tissue  forming.    After  this  recovery  was  rapid. 

Of  far  more  significance  are  those  infections  which 
result  in  the  condition  commonly  called  diabetic  gan- 
grene. Usually  the  course  of  events  is  that  the  patient 
first  notices  on  a  toe  or  the  ball  of  the  foot  a  little 
blister.  This  is  "  pricked  "  or  breaks  and  an  ulcer 
forms,  at  first  small  and  superficial  but  gradually 


220  DIABETES  MELLITUS 

larger  and  deeper  until  a  wide  eroded  area  exists,  in- 
volving fascia  and  tendons.  The  surrounding  tissue 
is  involved  in  the  inflammatory  reaction  and  becomes 
discolored  and  finally  livid.  In  some  cases  no  pulsa- 
tion can  be  felt  in  the  dorsalis  pedis  artery.  Surgical 
experience  has  demonstrated  that  amputation  is  a 
desperate  measure.  Many  cases  do  not  survive  the 
first  operation  or  when  they  do  it  is  so  often  found  that 
a  failure  of  healing  in  the  stump  necessitates  a  second 
operation  higher  up  the  leg.  One  surgeon  has  sum- 
marized his  experience  with  this  condition  in  the  dic- 
tum that  "amputation  of  the  foot  should  be  done  at 
the  hip."  Surgeons  in  general  admit  that  operative 
treatment  in  these  cases  is  most  unsatisfactory  and 
that  the  mortality  is  very  high.  On  this  account  it  is 
at  least  rational  to  give  some  other  method  a  pre- 
liminary trial  before  accepting  the  radical  and  des- 
perate course.  Surgical  measures  should  be  confined 
to  that  which  is  absolutely  necessary  and  can  be  done 
without  an  anaesthetic,  such  as  removing  dead  tissue 
from  the  ulcerated  area.  The  treatment  consists  in 
two  measures ;  an  appropriate  regimen  and  a  dressing 
to  the  foot,  which  should  be  kept  elevated.  For  the 
first  week  a  wet  dressing7  of  some  stimulating  so- 
lution is  best.  The  foot  must  be  kept  at  rest  ele- 
vated on  a  chair.    With  bad  cases  the  patient  must 

7  Red  wash  has  been  found  most  satisfactory. 


TREATMENT  221 

be  in  bed.  These  cases  are  easily  treated,  as  the  dia- 
betes is  usually  of  the  less  severe  types.  The  results 
are,  with  this  method,  hardly  less  than  brilliant.  A 
series  of  cases  was  published  by  Adrian  V.  S.  Lam- 
bert 8  and  some  of  these  patients  are  known  to  be  in 
excellent  health  at  present.  Gangrene  in  diabetes, 
while  it  has  many  points  of  similarity  with  that  ob- 
served in  senile  individuals,  is  not,  however,  very  often 
identical.  There  may  be,  often  is,  an  extreme  arterio- 
sclerosis but  apparently  there  are  other  factors,  per- 
haps angiospasm;  but  the  difference  rests  conspicu- 
ously in  the  primary  infection  with  the  diabetic.  That 
true  gangrene  resulting  from  an  endarteritis  ob- 
literans may  occur  in  diabetic  individuals  is  not  denied, 
though  this  is  exceptional,  the  important  fact  being 
that  the  types  of  gangrene  of  the  extremities  usually 
seen  in  association  with  diabetes  are  amenable  to 
treatment  without  amputation  of  the  diseased  part. 

Persons  afflicted  with  diabetes  are  subject  to  the 
same  surgical  diseases  as  the  rest  of  mankind.  The 
difference  here  lies  solely  in  the  increased  risk  of 
anaesthetics  and  of  the  operative  procedures.  It  is 
sometimes  a  matter  of  grave  doubt  whether  the 
patient  can  survive  on  account  of  a  complicating 
acidosis.  The  question  arises  then  as  to  how  to  de- 
termine whether  an  operation  can  be  undertaken  at  all, 

B  Annals  of  Surgery,  1914. 


222  DIABETES  MELLITXJS 

or  with  what  degree  of  increase  in  the  risk.  With 
a  young  diabetic  individual  who  manifests  a  con- 
siderable degree  of  acid  intoxication  it  may  be  stated 
with  confidence  that  an  anaesthetic  would  precipitate 
coma.  Whether  an  operation  can  be  considered  in  any 
case  depends  primarily  on  the  degree  of  acidosis  and 
this  may  best  be  indicated  by  the  ammonia  of  the 
urine.  If  the  ammonia  is  over  two  grammes  per  day 
a  severe  operation  would  be  hazardous  in  the  extreme ; 
if  three  grammes  per  day,  out  of  the  question.  It  is 
possible  with  some  cases  by  suitable  treatment  to  re- 
duce the  acidosis  to  an  amount  permitting  an  urgent 
surgical  procedure.  But  in  cases  of  this  type  it  must 
be  constantly  borne  in  mind  that  the  patient  is  not 
normal  and  the  post-operative  treatment  should  be 
directed  to  meet  a  developing  acidosis.  With  what 
has  already  been  said  relative  to  infections  further 
statement  is  hardly  demanded  to  point  out  the  ad- 
vantage of  suitable  dietetic  treatment  during  the  con- 
valescent period.  The  repair  of  the  wound  is  hastened 
and  the  possibility  of  infection  diminished. 


TREATMENT  223 

Fresh  Vegetables  that  Contain  Over  Five  Per  Cent, 
of  Carbohydrates. 

Gm.  equivalent 

Per  cent,  to  10  gm.  o  f  bread 

Radishes 5.0 

Leeks 6.0 

Mushrooms 6.0 

String  beans 6.0 

Turnips 6.0  90 

Kohl-rabi 7.0  76 

Oyster  plant 7.0  76 

Rutabaga 7.0  76 

Squash 8.0  66 

Beets 9.0  59 

Carrots 9.0  59 

Onions 9.0  56 

Parsnips 11.0  48 

Peas 15.0  35 

Lima  beans 22.0  24 

Potatoes 20.0  27 

Cora 19.0  27 

Canned  Vegetables  that  Contain  Over  Five  Per  Cent, 
op  Carbohydrates. 

Gm.  equivalent 

Per  cent,  to  10  gm.  of  bread 

Cora 18.0  29 

Succotash. 18.0  29 

Beans,  haricots  verts 2.0 

Tomatoes 3.0 

Peas 10.0  53 

Squash 10.0  53 

Beans,  haricots  flageolets 11.0  48 

Beans,  lima 13.0  41 

Beans,  baked 17.0  31 

Beans,  red  kidney 17.0  31 

Fresh  Fruits  that  Contain  Over  Five  Per  Cent,  of  Carbohydrates. 

Gm.  equivalent 

Per  cent,  to  10  gm.  of  bread. 

Strawberries 5.0  106 

Grape-fruit 6.0  88 

Watermelon 7.0  76 

Blackberries 8.0  66 

Cranberries 8.0  66 

Peaches 9.0  59 

Muskmelon 10.0  53 

Raspberries 10.0  53 

Apples 11.0  48 

Pears 11.0  48 

Apricots 12.0  44 

Gooseberries 12.0  44 

Pineapple 12.0  44 

Currants 13.0  41 

Oranges 13.0  41 

Huckleberries 17.0  31 

Bananas 20.0  27 


224  DIABETES  MELLITUS 

Nuts  that  Contain  Over  Five  Per  Cent,  of  Carbohydrates. 

Gm.  equivalent 
Per  cent,    to  10  gm.  of  bread. 

Butternuts 3.5 

Brazil-nuts 9.0  88 

Hickory-nuts 11.0  48 

Pecans 11.0  48 

Filberts 12.0  44 

Beechnuts 13.0  41 

Walnuts,  English 13.0  41 

Almonds 16.0  33 

Miscellaneous 

Plain  chocolate 25.0 

Cocoa 38.0 

Cocoa  nibs,  roasted 28.0 

Foods  Suitable  foe  Diabetic  Patients.9 
Under  Five  Per  Cent.  Carbohydrate. 

Milk,  sugar- free  (Whiting  and  Sons,  Rutherford  Ave.,  Boston)  . .  .0 

Marmalade,  casoid  sugarless   1.2 

Jam,  casoid  sugarless 2.1 

Dinner  rolls,  casoid  sugarless    2.2 

Casoid  flour   (Thomas  Leeming  and  Co.,  99  Chambers  St.,  New 

York)    2.2 

Gluten  biscuits  80  per  cent.    (Kellogg  Food  Co.,  Battle  Creek, 

Michigan)     4.4 

From  Five  to  Ten  Per  Cent.  Carbohydrate. 

Casoid  biscuits,  No.  2   5.6 

Rademanns  preserved  fruits  "  in  eigenem  Saft "  (Muller  and  Co., 

11  West  27th  St.,  New  York)  5.7 

Akoll  biscuits,  Huntley  and  Palmer  (Hazard  and  Co.,  29  Broad- 
way,  New  York)    6.5 

Rademanns   preserved   fruit  "  ohne  Zucker "    7.0 

Over  Ten  Per  Cent.  Carbohydrate. 

Proto  puffs,  No.  1    (Health  Food  Co.,  25  Lexington  Ave.,  New 

York)    H.9 

Plasmon  cocoa  (Plasmon  Co.,  London,  England)    20.9 

Soy  bean  flour  (Cereo  Co.,  Tappan,  N.  Y.)   23.7 

8  Analyses    from    Report    Conn.    Agriculture    Experiment    Station. 
Report  1913,  Part  I,  Section  1,  Diabetic  Foods. 


TREATMENT  225 

The  diabetic  patient  feels  the  restriction  in  his 
diet  mostly  in  the  absence  of  bread.  The  great  ma- 
jority of  gluten  breads  and  flours  are  shameful  frauds 
— and  are  absolutely  useless.  There  are  a  few  prepa- 
rations available  which  are  permissible,  and  a  list  of 
these  is  appended.  A  palatable  muffin  can  be  made 
from  soybean  flour  for  which  the  New  York  Hos- 
pital Diet  Kitchen  has  this  recipe : 

Soybean  Muffins 

1  cup  soybean  flour 

2  tablespoonfuls  wheat  flour 
y3  tablespoonful  salt 

2  teaspoonfuls  baking  powder 
Sift  all  together  and  add — 
%  cup  milk 

1  egg  beaten 

2  tablespoonfuls  melted  butter 

Pour  into  muffin  tins  and  bake  twenty  minutes. 

These  muffins  each  contain  10  grammes  of  car- 
bohydrate. 

Casoid  flour  may  be  used  advantageously  as  fol- 
lows: 

Casoid  Bread 

3  eggs 
Pinch  of  salt 

yz  cup  Casoid  flour 

Separate  whites  and  yolks;  add  salt  to  yolks;  beat  separately,  and 
add  yolks  to  whites.  Then  fold  in,  with  as  little  stirring  as  possible, 
the  flour.  Bake  in  a  greased  pan  with  a  hollow  centre,  such  as  is  used 
for  sponge  cake,  in  an  oven  not  too  hot  at  first  but  with  increasing  heat, 
for  twenty  minutes  or  half  an  hour.  If  not  allowed  to  cool  too  quickly 
it  will  retain  its  lightness  better. 

Recipe  by  Mrs.  Douglass  C.  Moriarta. 


XIV 
IDENTIFICATION  OF  SUGARS 

While  it  is  not  probable  that  any  mistake  ever 
occurs  in  identifying  glucose  in  the  urine  of  a  patient 
with  definite  symptoms  of  diabetes  the  misinterpreta- 
tion of  slight  reduction  tests  is,  however,  common.  It 
is  known,  too,  that  more  than  one  carbohydrate  may 
be  present  in  some  diabetic  urines.  The  following 
tests  are  of  service  in  recognizing  and  identifying 
small  amounts  of  sugar.  These  procedures  cannot 
well  be  undertaken  except  in  hospital  laboratories  and 
they  also  require  some  familiarity  with  chemical 
manipulations. 

Various  sugars  other  than  glucose  may  occur  in 
urine,  and  some  substances  not  sugar  can  simulate 
the  reducing  reactions  of  sugar.  Albumen  or  other 
proteins  must  before  the  tests  be  removed  from  the 
urine.  For  routine  examinations  of  urine  the  tests 
usually  employed  are  dependent  upon  reduction  of 
a  metallic  salt.  In  this  country  Fehling's  solution  is 
generally  given  preference.  When  carefully  manip- 
ulated Fehling's  solution  is  a  delicate  reagent  capable 
of  detecting  0.1  per  cent,  of  glucose.  It  reacts  to  all 
reducing  sugars  and  also  to  some  of  the  normal  in- 

226 


IDENTIFICATION  OF  SUGARS  227 

gredients  of  urine  such  as  uric  acid  and  creatinine, when 
these  are  present  in  some  degree  of  concentration. 
Several  methods  of  employing  Fehling's  solution  have 
been  advised  in  order  to  minimize  the  sources  of  error. 
The  solution  should  not  be  boiled  after  the  urine  is 
added ;  it  is  perhaps  the  best  way  to  allow  the  test  tube 
to  stand  in  a  boiling  water  bath.  Many  of  the  diffi- 
culties inherent  in  the  use  of  Fehling's  solution  for  rou- 
tine examinations  are  avoided  by  employing  Bene- 
dict's reagent.  Not  only  is  this  reagent  not  sensitive 
to  normal  urinary  ingredients  but  it  is  also  more 
delicate  than  Fehling's  in  its  response,  reducing  sugars 
reacting  to  as  low  as  0.01  per  cent,  of  glucose.  In  per- 
forming a  test  one  uses  about  5  c.c.  of  reagent  and  5  to 
10  drops  of  urine.  The  mixture  is  boiled  vigorously 
for  two  minutes  and  then  allowed  to  cool.  When  a  re- 
duction takes  place  there  separates  out  a  precipitate 
which  may  be  red,  yellow  or  greenish  in  color.  A 
slight  turbidity  which  may  form  without  precipitation 
is  due  to  urates  and  offers  no  source  of  confusion. 
This  reagent  does  not  react  to  uric  acid  nor  creatinine ; 
it  is,  however,  affected  by  glucuronic  acid. 

Some  urinary  substances  that  reduce  copper  salts 
do  not  reduce  bismuth  salts.  This  is  true  of  glucuronic 
and  homogentisic  acids,  and  accordingly  Nylander's 
solution  is  a  valuable  aid  in  differentiating  these  sub- 
stances from  sugar.    The  use  of  Nylander's  solution 


228  DIABETES  MELLITUS 

in  doubtful  cases  is  a  valuable  supplement  to  the  alka- 
line copper  solutions.  Protein  must  be  removed  from 
urine  before  conducting  tests  with  Nylander's  solu- 
tion. 

That  a  urine  gives  a  reduction  test  is  not  sufficient 
evidence  of  the  presence  of  sugar  even  when  the  re- 
action is  undoubted.  It  becomes  necessary  to  utilize 
other  tests  for  confirmation  and  among  these  fermen- 
tation and  polarization  are  of  chief  value. 

In  practice  it  is  customary  to  "run  controls"  on  all 
fermentation  tests — as  follows:  a  piece  of  brewer's 
yeast  the  size  of  a  pea  is  emulsified  with  5  c.c.  of  water. 
Two  drops  of  this  are  added  (1)  to  the  urine  to  be 
tested,  (2)  to  normal  urine,  (3)  to  normal  urine  which 
has  had  a  little  glucose  dissolved  in  it.  The  controls 
answer  the  questions :  does  the  yeast  alone  evolve  gas, 
and  is  it  capable  of  fermenting  glucose?  When  the 
sample  under  examination  evolves  gas  the  contents  of 
the  fermentation  tube  should  be  filtered  and  tested 
again  for  reduction  (and  rotation). 

Barfoed 
Monosaccharides  Reduction.       reaction.     Ferment.       Rotation. 

Pentoses +  000 

Hexoses,  Glucose +  +  +  d 

Levulose +  +  +  I 

Galactose +  4"  0  * 

Disaccharides 

Maltose +  0  +  5 

Lactose +  0  0  * 

Glucuronates +  0  0  / 

Glucuronic  acid +  0  0  6 


IDENTIFICATION  OF  SUGARS  229 

Sugars  may  be  divided  into  those  that  are  quickly 
fermented  at  a  temperature  of  38°  C.  (100°  F.)  with- 
in 18  hours  (glucose,  levulose,  maltose)  and  those 
that  require  24  to  36  hours  for  decomposition  (lactose, 
galactose,  isomaltose ) .  This  difference  may  some- 
times be  utilized  as  a  clue  in  tests  for  identification. 

There  is  no  gas  formation  with  pentose  nor  with 
the  glucuronic  acid  compounds  and  reduction  of  alka- 
line copper  solutions  will  occur  both  before  and  after 
fermentation.  Lactose  and  galactose  are  not  fer- 
mentable by  yeast  but  bacteria  present  in  commercial 
yeast  may  effect  decomposition. 

The  rotating  powers  of  the  various  sugars  serve  as 
important  evidence  towards  their  identification.  The 
following  classification  is  based  on  the  polarimetric 
action  of  these  substances.  Dextrorotatory:  glucose, 
galactose,  lactose,  maltose.  La^vorotatory :  levulose 
and  most  glucuronates  (oxybutyric  acid  and  proteins) . 
Inactive:  pentose. 

Polarimetric  readings  taken  both  before  and  after 
fermentation  frequently  offer  results  that  confirm 
other  tests.  If  only  glucose  or  levulose  be  present  the 
rotation  after  fermentation  is  the  rotation  of  normal 
urine  (1.,  .05°-.10°).  When  besides  glucose,  ^-oxy- 
butyric acid  or  glucuronic  acid  compounds  are  present 
in  the  urine  the  fermented  specimen  is  lasvorotatory. 


230  DIABETES  MELLITUS 

Maltose  deflects  polarized  light  more  than  does  glu- 
cose while  its  reducing  power  on  alkaline  copper  solu- 
tions is  much  less.  Hence  when  a  urine  containing 
maltose  is  examined  a  wide  discrepancy  between  the 
readings  and  titrations  is  noted  and  after  such  a  urine 
is  boiled  with  acid  the  polariscope  readings  decrease 
but  the  reduction  of  Fehling's  increases.  The  prosecu- 
tion of  these  tests  as  outlined  will  give  evidence  suffi- 
cient to  identify  the  sugars  commonly  found  in  urine ; 
for  complete  proof  confirmatory  reactions  are  de- 
manded. A  urine  which  causes  reduction  and  is 
dextrorotatory  before  fermentation  but  is  inactive 
afterwards  probably  contains  glucose. 

Before  applying  the  more  delicate  tests  for  the 
identification  of  sugars  it  saves  time  and  increases  the 
definiteness  of  these  tests  to  remove  from  the  urine  as 
much  of  the  nitrogenous  organic  matter  as  possible. 
This  may  be  done  in  several  ways:  (1)  basic  lead 
acetate  will  precipitate  pigments,  some  salts  and  glu- 
curonic acid.  The  excess  of  lead  is  removed  from  the 
filtrate  by  precipitating  with  hydrogen  sulphide.  (2) 
Mercuric  nitrate  precipitates  nitrogenous  materials 
quite  completely.  The  excess  of  mercury  is  removed 
from  the  filtrate  as  the  sulphide  with  H2S.  (3)  Phos- 
photungstic  acid  is  an  excellent  "clearing"  reagent; 
the  excess  being  precipitated  with  barium  hydrate 


IDENTIFICATION  OF  SUGARS  231 

from  the  filtrate  and  then  after  filtering  any  excess  of 
barium  is  thrown  down  by  C02.  Charcoal  cannot  be 
employed,  as  it  adsorbs  sugar  in  appreciable  amounts. 
By  using  one  of  these  preliminary  steps  a  water-clear 
material  is  secured  which  facilitates  the  tests  to  be  em- 
ployed. 

Barfoed  Reaction. — The  reagent  is  a  0.5  per 
cent,  solution  of  copper  acetate  in  0.1  per  cent,  acetic 
acidc  To  5  c.c.  of  this  reagent  add  10  drops  of  urine 
and  heat  in  a  water  bath  5  minutes.  A  yellowish  or 
reddish  precipitate  indicates  the  presence  of  sugar. 
This  reaction  is  characteristic  for  monosaccharides: 
glucose,  levulose,  and  galactose. 

Levulose. — SeliwanofF's  Reaction:  The  reagent 
consists  of  0.5  grammes  of  resorcin,  30  c.c.  of  con- 
centrated hydrochloric  acid  and  30  c.c.  of  water. 
Equal  parts  of  the  urine  and  this  reagent  are  mixed 
and  heated  on  the  water  bath.  When  levulose  is 
present  a  magenta  color  develops  promptly.  On  cool- 
ing a  red  precipitate  separates  out.  The  acid  may 
now  be  neutralized  with  sodium  carbonate  and  the 
solution  extracted  with  amyl  alcohol  to  which  is  im- 
parted a  red  color.  On  examining  with  the  spectro- 
scope a  band  appears  between  E  and  B. 

Pentose. — Orcin  Test;  Bial's  Method.  Reagent: 
100    c.c.    concentrated   hydrochloric    acid    (reagent, 


232  DIABETES  MELLITUS 

specific  gravity  1.195)  0.2  gramme  orcin,  and  5  drops 
of  a  10  per  cent,  solution  of  ferric  chloride.  Heat  5 
c.c.  of  this  reagent  to  boiling,  remove  from  the  flame 
and  add  the  urine  drop  by  drop,  using  not  over  1  c.c. 
The  characteristic  reaction  is  a  greenish  color  which 
appears  quite  promptly.  On  cooling,  the  mixture  is 
extracted  with  amyl  alcohol,  which  takes  up  a  blue- 
green  color.  An  absorption  band  between  C  and  D 
is  found  on  spectroscopic  examination.  Glucuronic 
acid  gives  the  same  result. 

Phloroglucin  Test:  See  under  Lactose. 

Lactose. — Malfetti-Wohlk  Test:  Mix  5  c.c.  of 
urine;  3-5  c.c.  of  strong  ammonia  and  5  drops  of 
potassium  hydroxide  (10  per  cent.).  The  mixture  is 
warmed  in  the  water  bath.  A  red  coloration  develops 
in  three  or  four  minutes.  This  reaction  is  also  given 
by  maltose.  With  glucose  the  color  is  brown  or  yel- 
lowish. 

Mucic  Acid  Test:  To  150  c.c.  of  urine  add  20  c.c. 
concentrated  nitric  acid  (specific  gravity  1.4)  and 
allow  to  stand  on  a  boiling  water  bath  until  the  ma- 
terial is  a  clear  yellow  color.  Allow  to  stand  24  hours 
in  a  cool  place.  Any  precipitate  that  has  formed  dur- 
ing this  time  is  filtered  off,  washed  with  cold  water 
and  dissolved  in  a  small  amount  of  boiling  water  from 
which  the  crystals  reform  on  cooling.  Mucic  acid  has 
a  melting  point  of  215°  to  225°,  depending  on  its 


IDENTIFICATION  OF  SUGARS  233 

purity.  On  dry  distillation  mucic  acid  yields  pyrrol, 
which  is  recognized  by  the  red  color  imparted  to  a 
pine  splinter  that  has  been  moistened  with  hydro- 
chloric acid.  The  mucic  acid  is  formed  from  galactose 
resulting  from  the  hydrolysis  of  lactose,  hence  the 
former  also  yields  the  test  as  well  as  the  latter. 

Phloroglucin  Test  (Salkowski) :  To  10  c.c.  of  con- 
centrated hydrochloric  add  enough  phloroglucin  so 
that  some  remains  undissolved  after  warming  the  mix- 
ture. Decant  the  acid  into  a  test  tube,  add  10  drops 
of  urine  and  place  the  test  tube  in  a  water  bath.  A 
positive  reaction  is  indicated  by  a  red  color  beginning 
above  and  extending  downward.  The  heating  must 
not  be  continued  after  the  color  has  appeared.  After 
cooling  the  pigment  may  be  extracted  with  amyl 
alcohol  and  examined  spectroscopically.  Pentose  and 
glucuronic  acid  yield  absorption  bands  between  D  and 
E;  lactose  and  galactose  none.  The  color  is  yielded 
by  lactose,  galactose,  pentose  and  glucuronic  acid. 

The  identification  of  a  sugar  cannot  be  completely 
established  without  the  aid  of  the  hydrazine  com- 
pounds. With  phenylhydrazine  and  with  substitution 
products  of  it  the  sugars  form  hydrazones  and  osa- 
zones  which,  in  their  solubilities,  melting  points,  and 
optical  activities,  are  characteristic. 

In  preparing  glucosazone  the  urine  may  be  used 

16 


234  DIABETES  MELLITUS 

without  previous  treatment  when  the  amount  of  sugar 
is  large ;  if  but  only  small  amounts  of  a  reducing  sub- 
stance be  present  it  is  advisable  first  to  remove  salts 
and  nitrogenous  matter  as  already  indicated  and  con- 
centrate the  material  before  conducting  the  tests. 

Glucosazone  may  be  prepared  as  follows:  Mix  5 
grammes  of  phenylhydrazine  hydrochloride,  10 
grammes  of  sodium  acetate,  and  10-15  c.c.  of  urine 
in  a  test  tube  and  warm ;  if  the  salts  do  not  all  dissolve 
add  more  water.  Allow  the  mixture  to  stand  in  hot 
water  for  half  an  hour  and  then  cool.  A  yellow 
crystalline  precipitate  of  glucosazone  separates  out. 
The  crystals  are  filtered  off  and  recrystallized  from 
hot  alcohol. 

Besides  the  compounds  formed  by  the  several 
sugars  with  phenalhydrazine,  there  are  various  hydra- 
zones  and  osazones  derived  from  diphenyl  and  methyl- 
phenylhydrazine.  These  all  differ  to  a  degree  in  their 
solubilities  in  water,  alcohol,  etc.,  which  fact  is  utilized 
in  separating  mixtures  of  sugars.  For  example  dex- 
trose forms  with  diphenylhydrazine  a  hydrazone  which 
is  insoluble  in  water ;  while  that  of  levulose  is  soluble. 
All  of  the  hydrazine  compounds  are  soluble  in  pyri- 
dine-alcohol  and  this  is  the  solvent  used  in  determin- 
ing the  specific  rotation:  0.2  gramme  of  the  osazone, 
4  grammes  of  pyridine  and  6  grammes  of  absolute 
ethyl  alcohol. 


IDENTIFICATION  OF  SUGARS 


235 


The  accompanying  chart  contains  the  data  ordi- 
narily required. 

OSAZONES  AND  HyDRAZONES 


Phenlyhydrazine. 

Melting  points. 

Solubility. 

Specific 
rotation. 

Melt 
at 

Methyl- 

phenyl- 

bydrazine. 

Diphenyl- 

Water. 

CH3OH 

hydrazine. 

Glucose 

I 
I 

sl 

100° 

1:90 

100° 

1:70 

100° 

1:4 

100° 

s 

60° 

sl 

sl 

sl 

s 

s 
s 
s 
s 
s 

-1.3° 
-1.3° 

+  .48° 

±0.0 
+1.3° 

+1.1° 
left 

205° 
205° 
195° 

210° 

205° 

150° 

165° 

115° 

130° 
160° 
180° 

164-173° 

162° 

Levulose 

Galactose 

157° 

Lactose 

Maltose 

Iso-maltose 

Pentose 

205-216° 

Glucuronic  acid .... 

s,  soluble;  I,  insoluble;  sl,  sb'gbtly  soluble. 

Nylander's  Test. — The  reagent  is  prepared  by 
dissolving  2  grammes  of  bismuth  subnitrate  and  4 
grammes  of  Rochelle  salt  in  100  c.c.  of  10  per  cent, 
potassium  hydroxide  solution.    The  reagent  is  filtered. 

To  5  c.c.  of  urine  in  a  test  tube  add  one-tenth  its 
volume  of  Nylander's  reagent  and  heat  for  five 
minutes  in  a  boiling  water  bath.  Reduction  is  in- 
dicated by  a  darkening  in  the  color  of  the  mixture 
due  to  the  precipitation  of  bismuth. 

Hsematoporphyrin,  indican,  urochrome,  and  uro- 
erythrin  may  be  sources  of  confusion. 


236  DIABETES  MELLITUS 

Fehling's  Solution. — Cupric  Sulphate  Solu- 
tion: Dissolve  34.65  grammes  of  cupric  sulphate  in 
water  and  make  up  to  500  c.c. 

Tartrate  Solution :  Dissolve  125  grammes  of  potas- 
sium hydroxide  and  173  grammes  of  Rochelle  salt  in 
water  and  dilute  to  500  c.c. 

These  solutions  should  be  filtered  and  kept  in 
rubber-stoppered  bottles.  Equal  volumes  are  mixed 
when  needed  for  tests. 

Benedict's  Reagent. — Qualitative : 

Copper  sulphate  (pure  crystallized)   17.3  gm. 

Sodium  or  potassium  citrate 173.0  gm. 

Sodium  carbonate  (crystallized)    200.0  gm. 

Distilled  water  to  make 1000.0  c.c. 

Dissolve  the  citrate  and  carbonate  together  with 
the  aid  of  heat  in  700  c.c.  of  water.  Filter  if  neces- 
sary. Dissolve  the  copper  sulphate  in  100  c.c.  of 
water  and  then  pour  slowly  into  the  first  solution  with 
constant  stirring.  After  cooling,  the  mixture  is  di- 
luted to  one  litre.  This  reagent  may  be  kept  indefi- 
nitely without  deterioration,  and  is  not  appreciably 
reduced  by  creatinine,  uric  acid,  the  simple  aldehydes, 
homogentisic  acid,  or  glucuronic  acid. 

Benedict's  Reagent. — Quantitative : 

Copper  sulphate   (pure  crystallized)    18.0  gm. 

Sodium  carbonate  (crystallized)  200.0  gm. 

Sodium  or  potassium  citrate 200.0  gm. 

Potassium  sulphocyanate   125.0  gm. 

Five  per  cent,  potassium  ferrocyanide  solution        5.0  c.c. 
Distilled  water  to  make 1000.0  c.c. 


IDENTIFICATION  OF  SUGARS  237 

With  the  aid  of  heat  dissolve  the  carbonate, 
citrate,  and  sulphocyanate  in  enough  water  to  make 
about  800.0  c.c.  of  the  mixture,  and  filter  if  necessary. 
Dissolve  the  copper  sulphate  in  100  c.c.  of  water  and 
pour  the  solution  slowly  into  the  other  liquid,  with 
constant  stirring.  Add  the  ferrocyanide,  cool,  and 
dilute  to  exactly  1  litre  (measuring  flask).  Of  the 
various  ingredients  the  copper  salt  only  need  be 
weighed  with  exactness.  25  c.c.  of  this  reagent  are 
reduced  by  50  mg.  of  glucose. 

The  urine,  10  c.c.  of  which  should  be  diluted  with 
water  to  100  c.c.  (unless  the  sugar  content  is  believed 
to  be  low),  is  poured  into  a  50  c.c.  burette  up  to  the 
zero  mark;  25  c.c.  of  the  reagent  are  measured  with 
a  pipette  into  a  porcelain  evaporation  dish  (25  to 
30  cm.  in  diameter) ,  10  to  20  grammes  of  crystallized 
sodium  carbonate  (or  one-half  the  weight  of  the  an- 
hydrous salt)  are  added,  together  with  a  small  quan- 
tity of  powdered  pumice  stone  or  talcum,  and  the 
mixture  heated  to  boiling  over  a  free  flame  until  the 
carbonate  has  entirely  dissolved.  The  diluted  urine 
is  now  run  in  from  the  burette,  rather  rapidly,  until 
a  chalk-white  precipitate  forms  and  the  blue  color  of 
the  mixture  begins  to  lessen  perceptibly,  after  which 
the  solution  from  the  burette  must  be  run  in,  a  few 
drops  at  a  time,  until  the  disappearance  of  the  last 
trace  of  blue  color,  which  marks  the  end-point.    The 


238  DIABETES  MELLITUS 

solution  must  be  kept  vigorously  boiling  throughout 
the  entire  titration.  If  the  mixture  becomes  too  con- 
centrated during  the  process,  water  may  be  added 
from  time  to  time  to  replace  the  volume  lost  by 
evaporation.  The  calculation  of  the  percentage  of 
sugar  in  the  original  sample  of  urine  is  very  simple. 
The  25  c.c.  of  copper  solution  are  reduced  by  exactly 
50  mg.  of  glucose.  Therefore  the  volume  run  out  of 
the  burette  to  effect  the  reduction  contained  50  mg. 
of  sugar.  When  the  urine  is  diluted  1  to  10,  as  in  the 
usual  titration  of  diabetic  urines,  the  formula  for  cal- 
culating the  percentage  of  sugar  is  the  following: 

5^?  X  1000  =  per    cent,    in    original    sample, 

wherein  x  is  the  number  of  cubic  centimetres  of  the 
diluted  urine  required  to  reduce  25  c.c.  of  the  copper 
solution. 

When  the  amount  of  sugar  is  small  the  volume  of 
urine  required  for  reduction  of  the  copper  may  impart 
to  the  reagent  a  confusing  color,  which  is  controlled 
nicely  by  adding  two  teaspoonfuls  of  powdered  cal- 
cium carbonate  to  the  reagent. 

DETERMINATION  OF  GLUCOSE  IN  BLOOD 

Benedict-Lewis  Method. — Following  is  the  pro- 
cedure for  glucose  estimation:  Two  c.c.  of  blood  (or 
less  if  desired)  are  aspirated  from  a  vein  through  a 
hypodermic  needle  and  a  piece  of  rubber  tubing  into 


IDENTIFICATION  OF  SUGARS  239 

an  Ostwald  pipette,  a  little  powdered  potassium  oxa- 
late in  the  tip  of  the  pipette  preventing  clotting.  The 
blood  is  drawn  up  a  little  above  the  mark  on  the 
pipette  and,  after  disconnecting  the  rubber  tubing,  is 
allowed  to  flow  back  to  the  mark.  Exactly  2  c.c.  are 
then  discharged  at  once  into  a  25  c.c.  volumetric  flask 
containing  5  c.c.  of  cold  water.  The  pipette  is  rinsed 
once  with  water  and  the  flask  is  shaken  well  to  insure 
thorough  mixing.  In  this  manner  the  blood  is  laked, 
a  matter  of  importance,  for  the  corpuscles  contain 
some  sugar  that  would  otherwise  be  lost.  Fifteen  c.c. 
of  saturated  picric  acid  solution  are  then  added,  the 
contents  of  the  flask  are  made  up  to  the  mark  with 
water  and  then  shaken.  After  filtration  8  c.c.  ali- 
quots  are  measured  out  into  large  Jena  test  tubes  for 
duplicate  determinations.  Two  c.c.  of  saturated 
picric  acid  solution  and  1  c.c.  of  10  per  cent,  sodium 
carbonate  are  added  (as  well  as  2  glass  beads  and  2  to 
3  drops  of  albolene)  and  the  contents  of  the  flask  are 
evaporated  rapidly  over  a  direct  flame  until  precipi- 
tation occurs.  About  5  c.c.  of  water  are  added,  the 
test  tube  is  again  heated  to  boiling  to  dissolve  the 
precipitate,  the  contents  of  the  tube  are  quantitatively 
transferred  to  a  10  c.c.  volumetric  flask,  cooled,  made 
up  to  the  mark,  shaken,  and  then  filtered  through 
cotton  into  the  colorimeter  chamber.  The  color  (set 
at  10  mm.)  is  compared  with  that  obtained  from  0.64 


240  DIABETES  MELLITUS 

mg.  of  dextrose,  using  5  c.c.  of  saturated  picric  acid 
and  1  c.c.  of  10  per  cent,  sodium  carbonate  proceeding 
in  the  manner  described  for  the  aliquot  of  the  blood 
filtrate.  Instead  of  running  a  "  standard  "  for  each 
determination  we  use  a  solution  of  picramic  acid  which 
has  been  standardized  against  the  color  obtained  from 
0.64  mg.  of  dextrose.  This  permanent  standard  will 
keep  indefinitely.  The  calculation  is,  of  course,  very- 
simple.  The  8  c.c.  aliquots  is  equivalent  to  0.64  c.c. 
of  blood. 

About  0.07  gm.  of  picramic  acid  is  treated  with 
about  25  c.c.  H20  and  0.2  gm.  Na2C03  warmed  until 
complete  solution  is  effected;  cooled  and  diluted  to 
one  litre.  The  solution  may  be  standardized  at  once 
and  will  keep  indefinitely. 


INDEX 


Acidosis,  59 

criteria  of,  150 

diabetic,  138 

experimental,  61 

measure  of,  135 

tests  for,  60 

theory  of,  65 
Acromegaly,  104 

Amino-acids,    as    dextrose    formers, 
20,  21 

in  normal  metabolism,  2 

from  protein,  19 

in  urine,  136 
Ammonia  excretion,  134 
Antiketonic  substances,  80 
Arterio-sclerosis,  167 

Barfoed's  reagent,  231 
Benedict's  reagent,  236 
Blood,  reaction  of,  154 

in  diabetes,  119 
Blood-sugar,  120 
state  of,  83 
/S-oxy butyric  acid  in  coma,'  152 

toxicity  of,  153 

see  also  ketones,  69 
Bronzed  diabetes,  107 

Carbohydrates  as  fuel,  9 

normal  oxidation  of,  31 
Cataract,  129 
Coma  diabeticum,  139 

diagnosis  of,  147 
theories  of,  150 
uraemic,  148 
Convulsions,  145 


Dextrose:    Nitrogen  ratio,  27 

in  diabetes,  178 

Lusk's,  57 

Minkowski's,  17 
Diabetes,  diagnosis  of,  159 

emotional  cause  of,  98 

etiology,  92 

gouty,  97 

history,  89 

incidence,  92 

inheritance  of,  95 

obesity  and,  97 

pregnancy  and,  99 

racial  predisposition,  93 
Diacetic  acid  (see  ketone  bodies), 
Diet,  bread  and  butter,  209 

oatmeal,  209 

potato,  209 

test,  184 

vegetable,  206 

Edema,  144 
Energy,  sources  of,  6 

Foods,  diabetic,  223 

Gastric  disease,  182 
Glands  of  internal  secretion,  53 
Glucosazone  test,  234 
Glucose,  from  fat,  85 

theory  of  over-production,  84 
Glycogen,  11 

from  protein,  14 

in  herbivora,  13 

sources  of,  10 

in  starvation,  13 

241 


242 


INDEX 


Glycosuria,  adrenal,  41 
causes,  82 

disappearance  of,  166 
due  to  drugs,  44 
duodenal,  46 
experimental,  36 
following    excision    of   pancreas, 

theory,  48,  52 
hypophyseal,  40 
pancreatic  atrophy,  47 
pancreatic,  experimental,  45 
jriq-dre,  37 
See  also  sugar 

Hemochromatosis,  107 
Heart,  lesions  of,  117 
Heat  of  body,  6 
Herpes  zoster,  129 
Hydrazones,  235 

Injuries  causing  diabetes,  101 
Islands  of  Langerhans,  110 

Ketone    bodies,     from    amino-acids, 
74 
from  fatty  acids,  74 
liver  and  formation  of,  68 
sources  of/ 72 
theory  of  formation,  70 
Ketonuria,  cause  of,  63 

induced  by  diet,  64,  137 
normal,  62 
phlorhizin,  64 
Kidney,  lesions  of,  118 

Lactic  acid,  as  glucose  former,  21 
Lactose,  tests  for,  232 
Levulose,  tests  for,  231 
Lipaemia,  122 

Liver,  glycogenic  function,  10 
lesions  of,  106 


Metabolism,  diabetic,  170 
amount  of,  174 
fasting,  5 
measure  of,  172 
normal,  1 

amount  of,  170 
water,  170 
Mucic  acid  test,  282 

Nephritis,  164 
Nervous  disorders,  128 

system,  injuries,  101 
Neuritis,  diabetic,  128 
Nitrogen  equilibrium,  4 

Osazones,  235 

Oxidation  of  amino-acids,  77 
of  fatty  acids,  75 

Pancreas,  excision  of,  18 

lesion  of,  108 
Pancreatic  glycosuria,  theory  of,  48, 

52 
Parabiosis,  49 

Pathogenesis  of  diabetes,  82,  86 
Pathology  of  diabetes,  101 
Pentose  tests,  231 
Polyuria,  125 
Pregnancy,  effect  of  diabetes  on,  131. 

160,  168 
Prognosis,  age  and,  163 
infections  and,  162 
Protein,  in  normal  metabolism,  3 
digestion  of,  19 

Quotient,  Lusk-Falta,  187 

Ratio,  dextrose:    Nitrogen,  17,  27,  57 
Renal  diabetes,  156 
Respiratory  quotient,  175 

Skin,  diseases  of,  127 


INDEX 


243 


Sugar,  from  fat,  23,  179 
from  protein,  15,  22 
estimation  of,  blood,  238 
identification,  226 
quantitative  estimations,  236 
tests  for,  in  urine,  227 
utilization  of,  178 

Symptoms,  124 

Treatment,  181 

of  acidosis,  210,  213 


Treatment  of  coma,  216 

of  diabetic  gangrene,  220 

of  mild  cases,  189 

principles  of,  183 

of  severe  cases,  203 

of  surgical  complications,  217 
Tumors  of  hypophysis,  104 

of  nervous  system,  102 

Uric  acid  excretion,  133 
Urine  in  diabetes,  132 


COLUMBIA  UNIVERSITY  LIBRARIES 

This  book  is  due  on  the  date  indicated  below,  or  at  the 
expiration  of  a  definite  period  after  the  date  of  borrowing,  as 
provided  by  the  rul^s  of  the  Library  or  by  special  arrange- 
ment with  the  Librarian  in  charge. 

DATE  BORROWED 

DATE  DUE 

DATE  BORROWED 

DATE  DUE 

■W 

MA 

*  4     195 

7 

/ 

1 

/yfe> 

► 

Cyf 

C2B(ll4l)M100 

RC660 

F81 

1915 


Foster  c#1 

Diabetes  mellitus. 


\ 


'*+ 


